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  • Review Article
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Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

Nature Reviews Cardiology volume 16, pages 361–378 (2019)Cite this article

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Abstract

The intact heart undergoes complex and multiscale remodelling processes in response to altered mechanical cues. Remodelling of the myocardium is regulated by a combination of myocyte and non-myocyte responses to mechanosensitive pathways, which can alter gene expression and therefore function in these cells. Cellular mechanotransduction and its downstream effects on gene expression are initially compensatory mechanisms during adaptations to the altered mechanical environment, but under prolonged and abnormal loading conditions, they can become maladaptive, leading to impaired function and cardiac pathologies. In this Review, we summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. Developments in systems modelling of the networks that regulate gene expression in response to mechanical stimuli should improve integrative understanding of their roles in vivo and help to discover new combinations of drugs and device therapies targeting mechanosignalling in heart disease.

Key points

  • The complex remodelling processes in the myocardium are regulated by mechanical signals that are sensed and transduced into transcriptional responses by cardiac myocytes and fibroblasts.

  • Mechanosensitive pathways regulate expression of genes that encode proteins mediating cardiac myocyte hypertrophy, myofibroblast differentiation and remodelling of the extracellular matrix.

  • Mathematical systems models are beginning to address outstanding challenges regarding how cardiac cells integrate complex mechanical and biochemical signals to coordinate gene expression and cell remodelling.

  • Integrative experimental and computational mechanotransduction studies should provide further insights into mechanisms and potential therapies for mechano-based diseases, including chronic tissue and chamber pathological remodelling.

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Fig. 1: Major mechanosensitive mechanisms and pathways in cardiac fibroblasts and myocytes.
Fig. 2: Systems model of the cardiac myocyte signalling network.

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References

  1. Azevedo, P. S., Polegato, B. F., Minicucci, M. F., Paiva, S. A. R. & Zornoff, L. A. M. Cardiac remodeling: concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arq. Bras. Cardiol. 106, 62–69 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Mann, D. L. Left ventricular size and shape: determinants of mechanical signal transduction pathways. Heart Fail. Rev. 10, 95–100 (2005).

    PubMed  Google Scholar 

  3. Swynghedauw, B. Darwinian evolution and cardiovascular remodeling. Heart Fail. Rev. 21, 795–802 (2016).

    PubMed  Google Scholar 

  4. Chiquet, M., Gelman, L., Lutz, R. & Maier, S. From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim. Biophys. Acta 1793, 911–920 (2009).

    CAS  PubMed  Google Scholar 

  5. Barry, S. P., Davidson, S. M. & Townsend, P. A. Molecular regulation of cardiac hypertrophy. Int. J. Biochem. Cell Biol. 40, 2023–2039 (2008).

    CAS  PubMed  Google Scholar 

  6. Ruwhof, C. & van der Laarse, A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc. Res. 47, 23–37 (2000).

    CAS  PubMed  Google Scholar 

  7. Russell, B., Motlagh, D. & Ashley, W. W. Form follows function: how muscle shape is regulated by work. J. Appl. Physiol. 88, 1127–1132 (2000).

    CAS  PubMed  Google Scholar 

  8. Braunwald, E. Heart failure. JACC Heart Fail. 1, 1–20 (2013).

    PubMed  Google Scholar 

  9. Rohini, A., Agrawal, N., Koyani, C. N. & Singh, R. Molecular targets and regulators of cardiac hypertrophy. Pharmacol. Res. 61, 269–280 (2010).

    CAS  PubMed  Google Scholar 

  10. Douglas, P. S., Morrow, R., Ioli, A. & Reichek, N. Left ventricular shape, afterload and survival in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 13, 311–315 (1989).

    CAS  PubMed  Google Scholar 

  11. Gupta, S., Das, B. & Sen, S. Cardiac hypertrophy: mechanisms and therapeutic opportunities. Antioxid. Redox Signal. 9, 623–652 (2007).

    CAS  PubMed  Google Scholar 

  12. Topkara, V. K. et al. Myocardial recovery in patients receiving contemporary left ventricular assist devices: results from the interagency registry for mechanically assisted circulatory support (INTERMACS). Circ. Heart Fail. 9, e003157 (2016).

    PubMed  Google Scholar 

  13. Heerdt, P. M. et al. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation 102, 2713–2719 (2000).

    CAS  PubMed  Google Scholar 

  14. Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).

    CAS  PubMed  Google Scholar 

  15. Humphrey, J. D., Dufresne, E. R. & Schwartz, M. A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol. 15, 802–812 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lyon, R. C., Zanella, F., Omens, J. H. & Sheikh, F. Mechanotransduction in cardiac hypertrophy and failure. Circ. Res. 116, 1462–1476 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Herum, K. M., Lunde, I. G., McCulloch, A. D. & Christensen, G. The soft- and hard-heartedness of cardiac fibroblasts: mechanotransduction signaling pathways in fibrosis of the heart. J. Clin. Med. 6, E53 (2017).

    PubMed  Google Scholar 

  18. Zeigler, A. C., Richardson, W. J., Holmes, J. W. & Saucerman, J. J. Computational modeling of cardiac fibroblasts and fibrosis. J. Mol. Cell. Cardiol. 93, 73–83 (2016).

    CAS  PubMed  Google Scholar 

  19. Civitarese, R. A., Kapus, A., McCulloch, C. A. & Connelly, K. A. Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: a dynamic relationship in cardiac biology and pathophysiology. Bas. Res. Cardiol. 112, 6 (2017).

    Google Scholar 

  20. Park, J. Y. et al. Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules. PLOS ONE 6, e22391 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, J. H., Thampatty, B. P., Lin, J. S. & Im, H. J. Mechanoregulation of gene expression in fibroblasts. Gene 391, 1–15 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lichter, J. G. et al. Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy. J. Mol. Cell. Cardiol. 72, 186–195 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Haque, Z. K. & Wang, D. Z. How cardiomyocytes sense pathophysiological stresses for cardiac remodeling. Cell. Mol. Life Sci. 74, 983–1000 (2017).

    CAS  PubMed  Google Scholar 

  24. Davis, J. et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. Cell 165, 1147–1159 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Plitt, G. D., Spring, J. T., Moulton, M. J. & Agrawal, D. K. Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction. Expert Rev. Cardiovasc. Ther. 16, 579–589 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kassi, M., Hannawi, B. & Trachtenberg, B. Recent advances in heart failure. Curr. Opin. Cardiol. 33, 249–256 (2018).

    PubMed  Google Scholar 

  27. Zhou, P. & Pu, W. T. Recounting cardiac cellular composition. Circ. Res. 118, 368–370 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Carter, W. G., Wayner, E. A., Bouchard, T. S. & Kaur, P. The role of integrins alpha 2 beta 1 and alpha 3 beta 1 in cell-cell and cell-substrate adhesion of human epidermal cells. J. Cell Biol. 110, 1387–1404 (1990).

    CAS  PubMed  Google Scholar 

  29. Babbitt, C. J., Shai, S. Y., Harpf, A. E., Pham, C. G. & Ross, R. S. Modulation of integrins and integrin signaling molecules in the pressure-loaded murine ventricle. Histochem. Cell Biol. 118, 431–439 (2002).

    CAS  PubMed  Google Scholar 

  30. Li, R. et al. beta1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses. Am. J. Pathol. 180, 952–962 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Traister, A. et al. Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function. Nat. Commun. 5, 4533 (2014).

    CAS  PubMed  Google Scholar 

  32. Kostin, S. et al. The internal and external protein scaffold of the T-tubular system in cardiomyocytes. Cell Tissue Res. 294, 449–460 (1998).

    CAS  PubMed  Google Scholar 

  33. Wang, N., Butler, J. P. & Ingber, D. E. Mechanotransduction across the cell surface and through the cytoskeleton. Science 260, 1124–1127 (1993).

    CAS  PubMed  Google Scholar 

  34. Kuppuswamy, D. et al. Association of tyrosine-phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium. J. Biol. Chem. 272, 4500–4508 (1997).

    CAS  PubMed  Google Scholar 

  35. Zhang, S. J., Truskey, G. A. & Kraus, W. E. Effect of cyclic stretch on beta1D-integrin expression and activation of FAK and RhoA. Am. J. Physiol. Cell Physiol. 292, C2057–C2069 (2007).

    CAS  PubMed  Google Scholar 

  36. Israeli-Rosenberg, S., Manso, A. M., Okada, H. & Ross, R. S. Integrins and integrin-associated proteins in the cardiac myocyte. Circ. Res. 114, 572–586 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zemljic-Harpf, A. E. et al. Heterozygous inactivation of the vinculin gene predisposes to stress-induced cardiomyopathy. Am. J. Pathol. 165, 1033–1044 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Manso, A. M. et al. Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload. J. Biol. Chem. 288, 4252–4264 (2013).

    CAS  PubMed  Google Scholar 

  39. Critchley, D. R. Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu. Rev. Biophys. 38, 235–254 (2009).

    CAS  PubMed  Google Scholar 

  40. Kovacic-Milivojevic, B. et al. Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy. Mol. Biol. Cell 12, 2290–2307 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Pham, C. G. et al. Striated muscle-specific beta(1D)-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway. Am. J. Physiol. Heart Circ. Physiol. 279, H2916–H2926 (2000).

    CAS  PubMed  Google Scholar 

  42. Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E. & Blaxall, B. C. Cardiac fibrosis: the fibroblast awakens. Circ. Res. 118, 1021–1040 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, S. H., Turnbull, J. & Guimond, S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J. Endocrinol. 209, 139–151 (2011).

    CAS  PubMed  Google Scholar 

  44. MacKenna, D., Summerour, S. R. & Villarreal, F. J. Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc. Res. 46, 257–263 (2000).

    CAS  PubMed  Google Scholar 

  45. Zaidel-Bar, R., Itzkovitz, S., Ma’ayan, A., Iyengar, R. & Geiger, B. Functional atlas of the integrin adhesome. Nat. Cell Biol. 9, 858–867 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Teoh, C. M., Tam, J. K. & Tran, T. Integrin and GPCR crosstalk in the regulation of ASM contraction signaling in asthma. J. Allergy 2012, 341282 (2012).

    Google Scholar 

  47. Margadant, C. & Sonnenberg, A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11, 97–105 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. MacKenna, D. A., Dolfi, F., Vuori, K. & Ruoslahti, E. Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblasts. J. Clin. Invest. 101, 301–310 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Herum, K. M., Choppe, J., Kumar, A., Engler, A. J. & McCulloch, A. D. Mechanical regulation of cardiac fibroblast profibrotic phenotypes. Mol. Biol. Cell 28, 1871–1882 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Seong, J. et al. Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins. Proc. Natl Acad. Sci. USA 110, 19372–19377 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  PubMed  Google Scholar 

  52. Davis, J. & Molkentin, J. D. Myofibroblasts: trust your heart and let fate decide. J. Mol. Cell. Cardiol. 70, 9–18 (2014).

    CAS  PubMed  Google Scholar 

  53. Molkentin, J. D. et al. Fibroblast-specific genetic manipulation of p38 mitogen-activated protein kinase in vivo reveals its central regulatory role in fibrosis. Circulation 136, 549–561 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Lapidos, K. A., Kakkar, R. & McNally, E. M. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ. Res. 94, 1023–1031 (2004).

    CAS  PubMed  Google Scholar 

  55. Jung, D., Yang, B., Meyer, J., Chamberlain, J. S. & Campbell, K. P. Identification and characterization of the dystrophin anchoring site on beta-dystroglycan. J. Biol. Chem. 270, 27305–27310 (1995).

    CAS  PubMed  Google Scholar 

  56. Ervasti, J. M. & Campbell, K. P. Dystrophin-associated glycoproteins: their possible roles in the pathogenesis of Duchenne muscular dystrophy. Mol. Cell Biol. Hum. Dis. Ser. 3, 139–166 (1993).

    CAS  PubMed  Google Scholar 

  57. Emery, A. E. Duchenne muscular dystrophy—Meryon’s disease. Neuromuscul. Disord. 3, 263–266 (1993).

    CAS  PubMed  Google Scholar 

  58. Towbin, J. A. et al. X-Linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87, 1854–1865 (1993).

    CAS  PubMed  Google Scholar 

  59. Lynch, G. S., Hinkle, R. T., Chamberlain, J. S., Brooks, S. V. & Faulkner, J. A. Force and power output of fast and slow skeletal muscles from mdx mice 6–28 months old. J. Physiol. 535, 591–600 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Barnabei, M. S. & Metzger, J. M. Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts. PLOS ONE 7, e32880 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Garbincius, J. F. & Michele, D. E. Dystrophin-glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling. Proc. Natl Acad. Sci. USA 112, 13663–13668 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Porter, J. D. et al. A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum. Mol. Genet. 11, 263–272 (2002).

    CAS  PubMed  Google Scholar 

  63. Chen, Y. W., Zhao, P., Borup, R. & Hoffman, E. P. Expression profiling in the muscular dystrophies: identification of novel aspects of molecular pathophysiology. J. Cell Biol. 151, 1321–1336 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Reed, A., Kohl, P. & Peyronnet, R. Molecular candidates for cardiac stretch-activated ion channels. Glob. Cardiol. Sci. Pract. 2014, 9–25 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Komuro, I. et al. Mechanical stretch activates the stress-activated protein kinases in cardiac myocytes. FASEB J. 10, 631–636 (1996).

    CAS  PubMed  Google Scholar 

  66. Sadoshima, J. & Izumo, S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 12, 1681–1692 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Sigurdson, W., Ruknudin, A. & Sachs, F. Calcium imaging of mechanically induced fluxes in tissue-cultured chick heart: role of stretch-activated ion channels. Am. J. Physiol. 262, H1110–H1115 (1992).

    CAS  PubMed  Google Scholar 

  68. Lyford, G. L. et al. alpha(1C) (Ca(V)1.2) L-type calcium channel mediates mechanosensitive calcium regulation. Am. J. Physiol. Cell Physiol. 283, C1001–1008 (2002).

    CAS  PubMed  Google Scholar 

  69. Peng, S.-Q., Hajela, R. K. & Atchison, W. D. Fluid flow-induced increase in inward Ba2+ current expressed in HEK293 cells transiently transfected with human neuronal L-type Ca2+ channels. Brain Res. 1045, 116–123 (2005).

    CAS  PubMed  Google Scholar 

  70. Rosa, A. O., Yamaguchi, N. & Morad, M. Mechanical regulation of native and the recombinant calcium channel. Cell Calcium 53, 264–274 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Katanosaka, Y. et al. TRPV2 is critical for the maintenance of cardiac structure and function in mice. Nat. Commun. 5, 3932 (2014).

    CAS  PubMed  Google Scholar 

  72. Teng, J., Loukin, S., Zhou, X. & Kung, C. Yeast luminometric and Xenopus oocyte electrophysiological examinations of the molecular mechanosensitivity of TRPV4. J. Vis. Exp. 82, 50816 (2013).

    Google Scholar 

  73. Qi, Y. et al. Uniaxial cyclic stretch stimulates TRPV4 to induce realignment of human embryonic stem cell-derived cardiomyocytes. J. Mol. Cell. Cardiol. 87, 65–73 (2015).

    CAS  PubMed  Google Scholar 

  74. Cadre, B. M. et al. Cyclic stretch down-regulates calcium transporter gene expression in neonatal rat ventricular myocytes. J. Mol. Cell. Cardiol. 30, 2247–2259 (1998).

    CAS  PubMed  Google Scholar 

  75. Jeong, D. et al. PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circ. Res. 102, 711–719 (2008).

    CAS  PubMed  Google Scholar 

  76. Finsen, A. V. et al. Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway. PLOS ONE 6, e28302 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Peyronnet, R., Nerbonne, J. M. & Kohl, P. Cardiac mechano-gated ion channels and arrhythmias. Circ. Res. 118, 311–329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Striessnig, J., Ortner, N. J. & Pinggera, A. Pharmacology of L-type calcium channels: novel drugs for old targets? Curr. Mol. Pharmacol. 8, 110–122 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Rog-Zielinska, E. A., Norris, R. A., Kohl, P. & Markwald, R. The living scar — cardiac fibroblasts and the injured heart. Trends Mol. Med. 22, 99–114 (2016).

    PubMed  PubMed Central  Google Scholar 

  80. Kamkin, A., Kiseleva, I. & Isenberg, G. Activation and inactivation of a non-selective cation conductance by local mechanical deformation of acutely isolated cardiac fibroblasts. Cardiovasc. Res. 57, 793–803 (2003).

    CAS  PubMed  Google Scholar 

  81. Kamkin, A. et al. Cardiac fibroblasts and the mechano-electric feedback mechanism in healthy and diseased hearts. Prog. Biophys. Mol. Biol. 82, 111–120 (2003).

    CAS  PubMed  Google Scholar 

  82. Numaga-Tomita, T. et al. TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Sci. Rep. 6, 39383 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Sharma, S. et al. TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation. Am. J. Physiol. Cell Physiol. 312, C562–C572 (2017).

    PubMed  PubMed Central  Google Scholar 

  84. Adapala, R. K. et al. TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J. Mol. Cell. Cardiol. 54, 45–52 (2013).

    CAS  PubMed  Google Scholar 

  85. Bers, D. M. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 70, 23–49 (2008).

    CAS  PubMed  Google Scholar 

  86. Chen-Izu, Y. & Izu, L. T. Mechano-chemo-transduction in cardiac myocytes. J. Physiol. 595, 3949–3958 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Ruwhof, C. et al. Mechanical stress stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes. Cell Calcium 29, 73–83 (2001).

    CAS  PubMed  Google Scholar 

  88. Gerdes, A. M. & Capasso, J. M. Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. J. Mol. Cell. Cardiol. 27, 849–856 (1995).

    CAS  PubMed  Google Scholar 

  89. Iribe, G. et al. Axial stretch of rat single ventricular cardiomyocytes causes an acute and transient increase in Ca2+ spark rate. Circ. Res. 104, 787–795 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Limbu, S., Hoang-Trong, T. M., Prosser, B. L., Lederer, W. J. & Jafri, M. S. Modeling local X-ROS and calcium signaling in the heart. Biophys. J. 109, 2037–2050 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Prosser, B. L., Ward, C. W. & Lederer, W. J. X-ROS signaling: rapid mechano-chemo transduction in heart. Science 333, 1440–1445 (2011).

    CAS  PubMed  Google Scholar 

  92. Allen, D. G. & Kentish, J. C. The cellular basis of the length-tension relation in cardiac muscle. J. Mol. Cell. Cardiol. 17, 821–840 (1985).

    CAS  PubMed  Google Scholar 

  93. Kurihara, S. & Komukai, K. Tension-dependent changes of the intracellular Ca2+ transients in ferret ventricular muscles. J. Physiol. 489, 617–625 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Morad, M., Javaheri, A., Risius, T. & Belmonte, S. Multimodality of Ca2+ signaling in rat atrial myocytes. Ann. NY Acad. Sci. 1047, 112–121 (2005).

    CAS  PubMed  Google Scholar 

  95. Gruver, C. L., DeMayo, F., Goldstein, M. A. & Means, A. R. Targeted developmental overexpression of calmodulin induces proliferative and hypertrophic growth of cardiomyocytes in transgenic mice. Endocrinology 133, 376–388 (1993).

    CAS  PubMed  Google Scholar 

  96. Zhang, C. L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Linseman, D. A. et al. Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca(2 + ) //calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J. Biol. Chem. 278, 41472–41481 (2003).

    CAS  PubMed  Google Scholar 

  98. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).

    CAS  PubMed  Google Scholar 

  99. Molkentin, J. D. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc. Res. 63, 467–475 (2004).

    CAS  PubMed  Google Scholar 

  100. Zobel, C. et al. Mechanisms of Ca2+-dependent calcineurin activation in mechanical stretch-induced hypertrophy. Cardiology 107, 281–290 (2007).

    CAS  PubMed  Google Scholar 

  101. Wu, Z., Wong, K., Glogauer, M., Ellen, R. P. & McCulloch, C. A. Regulation of stretch-activated intracellular calcium transients by actin filaments. Biochem. Biophys. Res. Commun. 261, 419–425 (1999).

    CAS  PubMed  Google Scholar 

  102. Rosen, L. B. & Greenberg, M. E. Stimulation of growth factor receptor signal transduction by activation of voltage-sensitive calcium channels. Proc. Natl Acad. Sci. USA 93, 1113–1118 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Iqbal, J. & Zaidi, M. Molecular regulation of mechanotransduction. Biochem. Biophys. Res. Commun. 328, 751–755 (2005).

    CAS  PubMed  Google Scholar 

  104. Davis, J., Burr, A. R., Davis, G. F., Birnbaumer, L. & Molkentin, J. D. A. TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev. Cell 23, 705–715 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. De Mello, W. C. & Danser, A. H. Angiotensin II and the heart: on the intracrine renin-angiotensin system. Hypertension 35, 1183–1188 (2000).

    PubMed  Google Scholar 

  106. Leenen, F. H., Skarda, V., Yuan, B. & White, R. Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors. Am. J. Physiol. 276, H317–H325 (1999).

    CAS  PubMed  Google Scholar 

  107. Sadoshima, J., Xu, Y., Slayter, H. S. & Izumo, S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, 977–984 (1993).

    CAS  PubMed  Google Scholar 

  108. Miyata, S., Haneda, T., Osaki, J. & Kikuchi, K. Renin-angiotensin system in stretch-induced hypertrophy of cultured neonatal rat heart cells. Eur. J. Pharmacol. 307, 81–88 (1996).

    CAS  PubMed  Google Scholar 

  109. Rosenkranz, S. TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc. Res. 63, 423–432 (2004).

    CAS  PubMed  Google Scholar 

  110. Yamazaki, T., Komuro, I. & Yazaki, Y. Molecular aspects of mechanical stress-induced cardiac hypertrophy. Mol. Cell. Biochem. 163, 197–201 (1996).

    PubMed  Google Scholar 

  111. Aikawa, R. et al. Rho family small G proteins play critical roles in mechanical stress-induced hypertrophic responses in cardiac myocytes. Circ. Res. 84, 458–466 (1999).

    CAS  PubMed  Google Scholar 

  112. McWhinney, C. D., Hunt, R. A., Conrad, K. M., Dostal, D. E. & Baker, K. M. The type I angiotensin II receptor couples to Stat1 and Stat3 activation through Jak2 kinase in neonatal rat cardiac myocytes. J. Mol. Cell. Cardiol. 29, 2513–2524 (1997).

    CAS  PubMed  Google Scholar 

  113. Pan, J. et al. Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ. Res. 84, 1127–1136 (1999).

    CAS  PubMed  Google Scholar 

  114. van Wamel, A. J., Ruwhof, C., van der Valk-Kokshoom, L. E., Schrier, P. I. & van der Laarse, A. The role of angiotensin II, endothelin-1 and transforming growth factor-beta as autocrine/paracrine mediators of stretch-induced cardiomyocyte hypertrophy. Mol. Cell. Biochem. 218, 113–124 (2001).

    PubMed  Google Scholar 

  115. Wang, T. L., Yang, Y. H., Chang, H. & Hung, C. R. Angiotensin II signals mechanical stretch-induced cardiac matrix metalloproteinase expression via JAK-STAT pathway. J. Mol. Cell. Cardiol. 37, 785–794 (2004).

    CAS  PubMed  Google Scholar 

  116. Zou, Y. et al. Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat. Cell Biol. 6, 499–506 (2004).

    CAS  PubMed  Google Scholar 

  117. Rakesh, K. et al. beta-Arrestin-biased agonism of the angiotensin receptor induced by mechanical stress. Sci. Signal. 3, ra46 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. Tang, W., Strachan, R. T., Lefkowitz, R. J. & Rockman, H. A. Allosteric modulation of β-arrestin-biased angiotensin II type 1 receptor signaling by membrane stretch. J. Biol. Chem. 289, 28271–28283 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Jiang, G. et al. Identification of amino acid residues in angiotensin II type 1 receptor sensing mechanical stretch and function in cardiomyocyte hypertrophy. Cell. Physiol. Biochem. 37, 105–116 (2015).

    CAS  PubMed  Google Scholar 

  120. Abraham, D. M. et al. β-arrestin mediates the Frank-Starling mechanism of cardiac contractility. Proc. Natl Acad. Sci. USA 113, 14426–14431 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Leri, A. et al. Stretch-mediated release of angiotensin II induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. J. Clin. Invest. 101, 1326–1342 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Shyu, K. G., Chen, C. C., Wang, B. W. & Kuan, P. Angiotensin II receptor antagonist blocks the expression of connexin43 induced by cyclical mechanical stretch in cultured neonatal rat cardiac myocytes. J. Mol. Cell. Cardiol. 33, 691–698 (2001).

    CAS  PubMed  Google Scholar 

  123. Zablocki, D. & Sadoshima, J. Solving the cardiac hypertrophy riddle: The angiotensin II-mechanical stress connection. Circ. Res. 113, 1192–1195 (2013).

    CAS  PubMed  Google Scholar 

  124. von Lueder, T. G. & Krum, H. RAAS inhibitors and cardiovascular protection in large scale trials. Cardiovasc. Drugs Ther. 27, 171–179 (2013).

    CAS  Google Scholar 

  125. Porter, K. E. & Turner, N. A. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol. Ther. 123, 255–278 (2009).

    CAS  PubMed  Google Scholar 

  126. Weber, K. T. Fibrosis in hypertensive heart disease: focus on cardiac fibroblasts. J. Hypertens. 22, 47–50 (2004).

    CAS  PubMed  Google Scholar 

  127. Staufenberger, S. et al. Angiotensin II type 1 receptor regulation and differential trophic effects on rat cardiac myofibroblasts after acute myocardial infarction. J. Cell. Physiol. 187, 326–335 (2001).

    CAS  PubMed  Google Scholar 

  128. Sun, Y., Zhang, J. Q., Zhang, J. & Ramires, F. J. Angiotensin II, transforming growth factor-beta1 and repair in the infarcted heart. J. Mol. Cell. Cardiol. 30, 1559–1569 (1998).

    CAS  PubMed  Google Scholar 

  129. Lee, A. A., Dillmann, W. H., McCulloch, A. D. & Villarreal, F. J. Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J. Mol. Cell. Cardiol. 27, 2347–2357 (1995).

    CAS  PubMed  Google Scholar 

  130. Gray, M. O., Long, C. S., Kalinyak, J. E., Li, H. T. & Karliner, J. S. Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc. Res. 40, 352–363 (1998).

    CAS  PubMed  Google Scholar 

  131. Campbell, S. E. & Katwa, L. C. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J. Mol. Cell. Cardiol. 29, 1947–1958 (1997).

    CAS  PubMed  Google Scholar 

  132. Pan, C. H., Wen, C. H. & Lin, C. S. Interplay of angiotensin II and angiotensin(1–7) in the regulation of matrix metalloproteinases of human cardiocytes. Exp. Physiol. 93, 599–612 (2008).

    CAS  PubMed  Google Scholar 

  133. Lijnen, P., Petrov, V., van Pelt, J. & Fagard, R. Inhibition of superoxide dismutase induces collagen production in cardiac fibroblasts. Am. J. Hypertens. 21, 1129–1136 (2008).

    CAS  PubMed  Google Scholar 

  134. Sano, M. et al. ERK and p38 MAPK, but not NF-kappaB, are critically involved in reactive oxygen species-mediated induction of IL-6 by angiotensin II in cardiac fibroblasts. Circ. Res. 89, 661–669 (2001).

    CAS  PubMed  Google Scholar 

  135. Yokoyama, T. et al. Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts. Am. J. Physiol. 276, H1968–H1976 (1999).

    CAS  PubMed  Google Scholar 

  136. Olson, E. R., Naugle, J. E., Zhang, X., Bomser, J. A. & Meszaros, J. G. Inhibition of cardiac fibroblast proliferation and myofibroblast differentiation by resveratrol. Am. J. Physiol. Heart Circ. Physiol. 288, H1131–H1138 (2005).

    CAS  PubMed  Google Scholar 

  137. Bouzegrhane, F. & Thibault, G. Is angiotensin II a proliferative factor of cardiac fibroblasts? Cardiovasc. Res. 53, 304–312 (2002).

    CAS  PubMed  Google Scholar 

  138. Chintalgattu, V., Harris, G. S., Akula, S. M. & Katwa, L. C. PPAR-gamma agonists induce the expression of VEGF and its receptors in cultured cardiac myofibroblasts. Cardiovasc. Res. 74, 140–150 (2007).

    CAS  PubMed  Google Scholar 

  139. Chao, H. H. et al. Inhibition of angiotensin II induced endothelin-1 gene expression by 17-beta-oestradiol in rat cardiac fibroblasts. Heart 91, 664–669 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Pauschinger, M. et al. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99, 2750–2756 (1999).

    CAS  PubMed  Google Scholar 

  141. Li, R. K. et al. Overexpression of transforming growth factor-beta1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation 96, 874–881 (1997).

    CAS  PubMed  Google Scholar 

  142. Wenzel, S., Taimor, G., Piper, H. M. & Schluter, K. D. Redox-sensitive intermediates mediate angiotensin II-induced p38 MAP kinase activation, AP-1 binding activity, and TGF-beta expression in adult ventricular cardiomyocytes. FASEB J. 15, 2291–2293 (2001).

    CAS  PubMed  Google Scholar 

  143. Brand, T. & Schneider, M. D. The TGF beta superfamily in myocardium: ligands, receptors, transduction, and function. J. Mol. Cell. Cardiol. 27, 5–18 (1995).

    CAS  PubMed  Google Scholar 

  144. Parker, T. G., Packer, S. E. & Schneider, M. D. Peptide growth factors can provoke “fetal” contractile protein gene expression in rat cardiac myocytes. J. Clin. Invest. 85, 507–514 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Koitabashi, N. et al. Pivotal role of cardiomyocyte TGF-beta signaling in the murine pathological response to sustained pressure overload. J. Clin. Invest. 121, 2301–2312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Banerjee, I. et al. Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing TGF-β signaling. J. Mol. Cell. Cardiol. 79, 133–144 (2015).

    CAS  PubMed  Google Scholar 

  147. Frangogiannis, N. G. The role of transforming growth factor (TGF)-beta in the infarcted myocardium. J. Thorac. Dis. 9, S52–S63 (2017).

    PubMed  PubMed Central  Google Scholar 

  148. Biernacka, A., Dobaczewski, M. & Frangogiannis, N. G. TGF-beta signaling in fibrosis. Growth Factors 29, 196–202 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Eghbali, M., Tomek, R., Sukhatme, V. P., Woods, C. & Bhambi, B. Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRNAs and expression of early transcription factors. Circ. Res. 69, 483–490 (1991).

    CAS  PubMed  Google Scholar 

  150. Shi, Y. & Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).

    CAS  PubMed  Google Scholar 

  151. Feng, X. H. & Derynck, R. Specificity and versatility in tgf-beta signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005).

    CAS  PubMed  Google Scholar 

  152. Chen, W. & Frangogiannis, N. G. Fibroblasts in post-infarction inflammation and cardiac repair. Biochim. Biophys. Acta 1833, 945–953 (2013).

    CAS  PubMed  Google Scholar 

  153. Lee, A. A., Delhaas, T., McCulloch, A. D. & Villarreal, F. J. Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns. J. Mol. Cell. Cardiol. 31, 1833–1843 (1999).

    CAS  PubMed  Google Scholar 

  154. Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. van Putten, S., Shafieyan, Y. & Hinz, B. Mechanical control of cardiac myofibroblasts. J. Mol. Cell. Cardiol. 93, 133–142 (2016).

    PubMed  Google Scholar 

  156. Jenkins, G. The role of proteases in transforming growth factor-beta activation. Int. J. Biochem. Cell Biol. 40, 1068–1078 (2008).

    CAS  PubMed  Google Scholar 

  157. Husse, B., Briest, W., Homagk, L., Isenberg, G. & Gekle, M. Cyclical mechanical stretch modulates expression of collagen I and collagen III by PKC and tyrosine kinase in cardiac fibroblasts. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1898–R1907 (2007).

    CAS  PubMed  Google Scholar 

  158. Tyagi, S. C. et al. Stretch-induced membrane type matrix metalloproteinase and tissue plasminogen activator in cardiac fibroblast cells. J. Cell. Physiol. 176, 374–382 (1998).

    CAS  PubMed  Google Scholar 

  159. Flynn, B. P. et al. Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8). PLOS ONE 5, e12337 (2010).

    PubMed  PubMed Central  Google Scholar 

  160. Chang, S. W., Flynn, B. P., Ruberti, J. W. & Buehler, M. J. Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown. Biomaterials 33, 3852–3859 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Yang, J. et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat. Commun. 7, 13710 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Gautel, M. The sarcomeric cytoskeleton: who picks up the strain? Curr. Opin. Cell Biol. 23, 39–46 (2011).

    CAS  PubMed  Google Scholar 

  163. Spudich, J. A. The myosin swinging cross-bridge model. Nat. Rev. Mol. Cell Biol. 2, 387–392 (2001).

    CAS  PubMed  Google Scholar 

  164. Frank, D. & Frey, N. Cardiac Z-disc signaling network. J. Biol. Chem. 286, 9897–9904 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Granzier, H. L. & Labeit, S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ. Res. 94, 284–295 (2004).

    CAS  PubMed  Google Scholar 

  166. Anderson, B. R. & Granzier, H. L. Titin-based tension in the cardiac sarcomere: molecular origin and physiological adaptations. Prog. Biophys. Mol. Biol. 110, 204–217 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Hoshijima, M. Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures. Am. J. Physiol. Heart Circ. Physiol. 290, H1313–H1325 (2006).

    CAS  PubMed  Google Scholar 

  168. Arber, S., Halder, G. & Caroni, P. Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell 79, 221–231 (1994).

    CAS  PubMed  Google Scholar 

  169. Heineke, J. et al. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc. Natl Acad. Sci. USA 102, 1655–1660 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Knoll, R. et al. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111, 943–955 (2002).

    CAS  PubMed  Google Scholar 

  171. Chang, D. F. et al. Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors. Dev. Cell 4, 107–118 (2003).

    CAS  PubMed  Google Scholar 

  172. Linke, W. A. & Kruger, M. The giant protein titin as an integrator of myocyte signaling pathways. Physiology 25, 186–198 (2010).

    CAS  PubMed  Google Scholar 

  173. Sheikh, F. et al. An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J. Clin. Invest. 118, 3870–3880 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Chu, P. H., Ruiz-Lozano, P., Zhou, Q., Cai, C. & Chen, J. Expression patterns of FHL/SLIM family members suggest important functional roles in skeletal muscle and cardiovascular system. Mech. Dev. 95, 259–265 (2000).

    CAS  PubMed  Google Scholar 

  175. Gaussin, V. et al. Common genomic response in different mouse models of beta-adrenergic-induced cardiomyopathy. Circulation 108, 2926–2933 (2003).

    CAS  PubMed  Google Scholar 

  176. Raskin, A. et al. A novel mechanism involving four-and-a-half LIM domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics. J. Biol. Chem. 287, 29273–29284 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Miller, M. K. et al. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J. Mol. Biol. 333, 951–964 (2003).

    CAS  PubMed  Google Scholar 

  178. Barash, I. A., Mathew, L., Ryan, A. F., Chen, J. & Lieber, R. L. Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse. Am. J. Physiol. Cell Physiol. 286, C355–C364 (2004).

    CAS  PubMed  Google Scholar 

  179. Lun, A. S., Chen, J. & Lange, S. Probing muscle ankyrin-repeat protein (MARP) structure and function. Anat. Rec. 297, 1615–1629 (2014).

    CAS  Google Scholar 

  180. Ingber, D. E., Wang, N. & Stamenovic, D. Tensegrity, cellular biophysics, and the mechanics of living systems. Rep. Prog. Phys. 77, 046603 (2014).

    PubMed  PubMed Central  Google Scholar 

  181. Amano, M., Nakayama, M. & Kaibuchi, K. Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton 67, 545–554 (2010).

    CAS  PubMed  Google Scholar 

  182. Mouilleron, S., Langer, C. A., Guettler, S., McDonald, N. Q. & Treisman, R. Structure of a pentavalent G-actin*MRTF-A complex reveals how G-actin controls nucleocytoplasmic shuttling of a transcriptional coactivator. Sci. Signal. 4, ra40 (2011).

    PubMed  Google Scholar 

  183. Small, E. M. et al. Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ. Res. 107, 294–304 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Codelia, V. A., Sun, G. & Irvine, K. D. Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr. Biol. 24, 2012–2017 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    CAS  PubMed  Google Scholar 

  186. Muehlich, S., Rehm, M., Ebenau, A. & Goppelt-Struebe, M. Synergistic induction of CTGF by cytochalasin D and TGFbeta-1 in primary human renal epithelial cells: role of transcriptional regulators MKL1, YAP/TAZ and Smad2/3. Cell. Signal. 29, 31–40 (2017).

    CAS  PubMed  Google Scholar 

  187. Liu, F. et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L344–L357 (2015).

    CAS  PubMed  Google Scholar 

  188. Chan, M. W., Hinz, B. & McCulloch, C. A. Mechanical induction of gene expression in connective tissue cells. Methods Cell Biol. 98, 178–205 (2010).

    PubMed  Google Scholar 

  189. Fedorchak, G. R., Kaminski, A. & Lammerding, J. Cellular mechanosensing: getting to the nucleus of it all. Prog. Biophys. Mol. Biol. 115, 76–92 (2014).

    PubMed  PubMed Central  Google Scholar 

  190. Crisp, M. et al. Coupling of the nucleus and cytoplasm: role of the LINC complex. J. Cell Biol. 172, 41–53 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Lammerding, J., Kamm, R. D. & Lee, R. T. Mechanotransduction in cardiac myocytes. Ann. NY Acad. Sci. 1015, 53–70 (2004).

    PubMed  Google Scholar 

  192. Enyedi, B. & Niethammer, P. Nuclear membrane stretch and its role in mechanotransduction. Nucleus 8, 156–161 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Caputo, S. et al. The carboxyl-terminal nucleoplasmic region of MAN1 exhibits a DNA binding winged helix domain. J. Biol. Chem. 281, 18208–18215 (2006).

    CAS  PubMed  Google Scholar 

  194. Chang, W., Worman, H. J. & Gundersen, G. G. Accessorizing and anchoring the LINC complex for multifunctionality. J. Cell Biol. 208, 11–22 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Guilluy, C. et al. Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell Biol. 16, 376–381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Cupesi, M. et al. Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse. J. Mol. Cell. Cardiol. 48, 1290–1297 (2010).

    CAS  PubMed  Google Scholar 

  197. Enyedi, B., Jelcic, M. & Niethammer, P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell 165, 1160–1170 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Schreiber, K. H. & Kennedy, B. K. When lamins go bad: nuclear structure and disease. Cell 152, 1365–1375 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Komaki, H. et al. Inflammatory changes in infantile-onset LMNA-associated myopathy. Neuromuscul. Disord. 21, 563–568 (2011).

    PubMed  Google Scholar 

  200. Iyer, K. V., Pulford, S., Mogilner, A. & Shivashankar, G. V. Mechanical activation of cells induces chromatin remodeling preceding MKL nuclear transport. Biophys. J. 103, 1416–1428 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Furusawa, T. et al. Chromatin decompaction by the nucleosomal binding protein HMGN5 impairs nuclear sturdiness. Nat. Commun. 6, 6138 (2015).

    CAS  PubMed  Google Scholar 

  202. Rochman, M. et al. The interaction of NSBP1/HMGN5 with nucleosomes in euchromatin counteracts linker histone-mediated chromatin compaction and modulates transcription. Mol. Cell 35, 642–656 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Nikolova, V. et al. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J. Clin. Invest. 113, 357–369 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Ho, C. Y., Jaalouk, D. E., Vartiainen, M. K. & Lammerding, J. Lamin A/C and emerin regulate MKL1-SRF activity by modulating actin dynamics. Nature 497, 507–511 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Thomas, C. H., Collier, J. H., Sfeir, C. S. & Healy, K. E. Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc. Natl Acad. Sci. USA 99, 1972–1977 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Alam, S. G. et al. The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity. Sci. Rep. 6, 38063 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Lovett, D. B., Shekhar, N., Nickerson, J. A., Roux, K. J. & Lele, T. P. Modulation of nuclear shape by substrate rigidity. Cell. Mol. Bioeng. 6, 230–238 (2013).

    CAS  PubMed  Google Scholar 

  208. Vermij, S. H., Abriel, H. & van Veen, T. A. Refining the molecular organization of the cardiac intercalated disc. Cardiovasc. Res. 113, 259–275 (2017).

    CAS  PubMed  Google Scholar 

  209. Sheikh, F., Ross, R. S. & Chen, J. Cell-cell connection to cardiac disease. Trends Cardiovasc. Med. 19, 182–190 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Yoshida, M. et al. Weaving hypothesis of cardiomyocyte sarcomeres: discovery of periodic broadening and narrowing of intercalated disk during volume-load change. Am. J. Pathol. 176, 660–678 (2010).

    PubMed  PubMed Central  Google Scholar 

  211. Mezzano, V. & Sheikh, F. Cell-cell junction remodeling in the heart: possible role in cardiac conduction system function and arrhythmias? Life Sci. 90, 313–321 (2012).

    CAS  PubMed  Google Scholar 

  212. Michaelson, J. E. & Huang, H. Cell-cell junctional proteins in cardiovascular mechanotransduction. Ann. Biomed. Engineer. 40, 568–577 (2012).

    Google Scholar 

  213. Chopra, A., Tabdanov, E., Patel, H., Janmey, P. A. & Kresh, J. Y. Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing. Am. J. Physiol. Heart Circ. Physiol. 300, H1252–H1266 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Kostetskii, I. et al. Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ. Res. 96, 346–354 (2005).

    CAS  PubMed  Google Scholar 

  215. Yonemura, S., Wada, Y., Watanabe, T., Nagafuchi, A. & Shibata, M. alpha-Catenin as a tension transducer that induces adherens junction development. Nat. Cell Biol. 12, 533–542 (2010).

    CAS  PubMed  Google Scholar 

  216. Vite, A., Zhang, C., Yi, R., Emms, S. & Radice, G. L. alpha-Catenin-dependent cytoskeletal tension controls Yap activity in the heart. Development 145, dev149823 (2018).

    PubMed  PubMed Central  Google Scholar 

  217. Sheikh, F. et al. alpha-E-catenin inactivation disrupts the cardiomyocyte adherens junction, resulting in cardiomyopathy and susceptibility to wall rupture. Circulation 114, 1046–1055 (2006).

    CAS  PubMed  Google Scholar 

  218. Ehler, E. et al. Alterations at the intercalated disk associated with the absence of muscle LIM protein. J. Cell Biol. 153, 763–772 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Zhang, J. Q. et al. Ultrastructural and biochemical localization of N-RAP at the interface between myofibrils and intercalated disks in the mouse heart. Biochemistry 40, 14898–14906 (2001).

    CAS  PubMed  Google Scholar 

  220. Hariharan, V. et al. Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion. Cardiovasc. Res. 104, 280–289 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Yang, Z. et al. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ. Res. 99, 646–655 (2006).

    CAS  PubMed  Google Scholar 

  222. Lyon, R. C. et al. Connexin defects underlie arrhythmogenic right ventricular cardiomyopathy in a novel mouse model. Hum. Mol. Genet. 23, 1134–1150 (2014).

    CAS  PubMed  Google Scholar 

  223. Pilichou, K. et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113, 1171–1179 (2006).

    CAS  PubMed  Google Scholar 

  224. Salameh, A. et al. Opposing and synergistic effects of cyclic mechanical stretch and alpha- or beta-adrenergic stimulation on the cardiac gap junction protein Cx43. Pharmacol. Res. 62, 506–513 (2010).

    CAS  PubMed  Google Scholar 

  225. Zhuang, J., Yamada, K. A., Saffitz, J. E. & Kleber, A. G. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ. Res. 87, 316–322 (2000).

    CAS  PubMed  Google Scholar 

  226. Wang, Q. et al. Xin proteins and intercalated disc maturation, signaling and diseases. Front. Biosci. 17, 2566–2593 (2012).

    PubMed Central  Google Scholar 

  227. Chilton, L. et al. K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. Am. J. Physiol. Heart Circ. Physiol. 288, H2931–H2939 (2005).

    CAS  PubMed  Google Scholar 

  228. Miragoli, M., Gaudesius, G. & Rohr, S. Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ. Res. 98, 801–810 (2006).

    CAS  PubMed  Google Scholar 

  229. Rohr, S. Myofibroblasts in diseased hearts: new players in cardiac arrhythmias? Heart Rhythm 6, 848–856 (2009).

    PubMed  Google Scholar 

  230. Kohl, P., Camelliti, P., Burton, F. L. & Smith, G. L. Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation. J. Electrocardiol. 38, 45–50 (2005).

    PubMed  Google Scholar 

  231. Zlochiver, S. et al. Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. Biophys. J. 95, 4469–4480 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Rohr, S. Arrhythmogenic implications of fibroblast-myocyte interactions. Circ. Arrhythm. Electrophysiol. 5, 442–452 (2012).

    PubMed  Google Scholar 

  233. Quinn, T. A. et al. Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics. Proc. Natl Acad. Sci. USA 113, 14852–14857 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Ongstad, E. & Kohl, P. Fibroblast-myocyte coupling in the heart: potential relevance for therapeutic interventions. J. Mol. Cell. Cardiol. 91, 238–246 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Roell, W. et al. Overexpression of Cx43 in cells of the myocardial scar: correction of post-infarct arrhythmias through heterotypic cell-cell coupling. Sci. Rep. 8, 7145 (2018).

    PubMed  PubMed Central  Google Scholar 

  236. Shyu, K. G., Ko, W. H., Yang, W. S., Wang, B. W. & Kuan, P. Insulin-like growth factor-1 mediates stretch-induced upregulation of myostatin expression in neonatal rat cardiomyocytes. Cardiovasc. Res. 68, 405–414 (2005).

    CAS  PubMed  Google Scholar 

  237. Pemberton, C. J., Raudsepp, S. D., Yandle, T. G., Cameron, V. A. & Richards, A. M. Plasma cardiotrophin-1 is elevated in human hypertension and stimulated by ventricular stretch. Cardiovasc. Res. 68, 109–117 (2005).

    CAS  PubMed  Google Scholar 

  238. Bowers, S. L. K., Borg, T. K. & Baudino, T. A. The dynamics of fibroblast–myocyte–capillary interactions in the heart. Ann. NY Acad. Sci. 1188, 143–152 (2010).

    PubMed  Google Scholar 

  239. Weinberg, E. O. et al. Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload. Physiol. Genom. 12, 113–127 (2003).

    CAS  Google Scholar 

  240. Wang, D. et al. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 42, 88–95 (2003).

    CAS  PubMed  Google Scholar 

  241. Miyazaki, H. et al. Comparison of gene expression profiling in pressure and volume overload-induced myocardial hypertrophies in rats. Hypertens. Res. 29, 1029–1045 (2006).

    CAS  PubMed  Google Scholar 

  242. Zheng, J. et al. Microarray identifies extensive downregulation of noncollagen extracellular matrix and profibrotic growth factor genes in chronic isolated mitral regurgitation in the dog. Circulation 119, 2086–2095 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Blaxall, B. C., Tschannen-Moran, B. M., Milano, C. A. & Koch, W. J. Differential gene expression and genomic patient stratification following left ventricular assist device support. J. Am. Coll. Cardiol. 41, 1096–1106 (2003).

    CAS  PubMed  Google Scholar 

  244. Birks, E. J. et al. Gene profiling changes in cytoskeletal proteins during clinical recovery after left ventricular-assist device support. Circulation 112, I57–64 (2005).

    PubMed  Google Scholar 

  245. Margulies, K. B. et al. Mixed messages: transcription patterns in failing and recovering human myocardium. Circ. Res. 96, 592–599 (2005).

    CAS  PubMed  Google Scholar 

  246. Matkovich, S. J. et al. Reciprocal regulation of myocardial microRNAs and messenger RNA in human cardiomyopathy and reversal of the microRNA signature by biomechanical support. Circulation 119, 1263–1271 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Yang, K. C. et al. Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support. Circulation 129, 1009–1021 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Terracciano, C. M. et al. Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy. Circulation 109, 2263–2265 (2004).

    CAS  PubMed  Google Scholar 

  249. Weinberg, E. O. et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106, 2961–2966 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Kakkar, R. & Lee, R. T. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat. Rev. Drug Discov. 7, 827–840 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. de Boer, R. A., Daniels, L. B., Maisel, A. S. & Januzzi, J. L. Jr. State of the Art: Newer biomarkers in heart failure. Eur. J. Heart Fail. 17, 559–569 (2015).

    PubMed  Google Scholar 

  252. Frank, D. et al. Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 51, 309–318 (2008).

    CAS  PubMed  Google Scholar 

  253. McCain, M. L., Sheehy, S. P., Grosberg, A., Goss, J. A. & Parker, K. K. Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc. Natl Acad. Sci. USA 110, 9770–9775 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Rysa, J., Tokola, H. & Ruskoaho, H. Mechanical stretch induced transcriptomic profiles in cardiac myocytes. Sci. Rep. 8, 4733 (2018).

    PubMed  PubMed Central  Google Scholar 

  255. Kessler, D. et al. Fibroblasts in mechanically stressed collagen lattices assume a “synthetic” phenotype. J. Biol. Chem. 276, 36575–36585 (2001).

    CAS  PubMed  Google Scholar 

  256. Driesen, R. B. et al. Reversible and irreversible differentiation of cardiac fibroblasts. Cardiovasc. Res. 101, 411–422 (2014).

    CAS  PubMed  Google Scholar 

  257. Haggart, C. R., Ames, E. G., Lee, J. K. & Holmes, J. W. Effects of stretch and shortening on gene expression in intact myocardium. Physiol. Genomics 46, 57–65 (2014).

    PubMed  Google Scholar 

  258. Hirt, M. N. et al. Increased afterload induces pathological cardiac hypertrophy: a new in vitro model. Bas. Res. Cardiol. 107, 307 (2012).

    Google Scholar 

  259. Boon, R. A. & Dimmeler, S. MicroRNAs in myocardial infarction. Nat. Rev. Cardiol. 12, 135–142 (2015).

    CAS  PubMed  Google Scholar 

  260. van Rooij, E. et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc. Natl Acad. Sci. USA 103, 18255–18260 (2006).

    PubMed  PubMed Central  Google Scholar 

  261. Frank, D. et al. MicroRNA-20a inhibits stress-induced cardiomyocyte apoptosis involving its novel target Egln3/PHD3. J. Mol. Cell. Cardiol. 52, 711–717 (2012).

    CAS  PubMed  Google Scholar 

  262. van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007).

    PubMed  Google Scholar 

  263. Callis, T. E. et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J. Clin. Invest. 119, 2772–2786 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Shyu, K. G., Wang, B. W., Wu, G. J., Lin, C. M. & Chang, H. Mechanical stretch via transforming growth factor-beta1 activates microRNA208a to regulate endoglin expression in cultured rat cardiac myoblasts. Eur. J. Heart Fail. 15, 36–45 (2013).

    CAS  PubMed  Google Scholar 

  265. Wang, B. W., Wu, G. J., Cheng, W. P. & Shyu, K. G. Mechanical stretch via transforming growth factor-beta1 activates microRNA-208a to regulate hypertrophy in cultured rat cardiac myocytes. J. Formos. Med. Assoc. 112, 635–643 (2013).

    CAS  PubMed  Google Scholar 

  266. Ransohoff, J. D., Wei, Y. & Khavari, P. A. The functions and unique features of long intergenic non-coding RNA. Nat. Rev. Mol. Cell Biol. 19, 143–157 (2018).

    CAS  PubMed  Google Scholar 

  267. Sallam, T., Sandhu, J. & Tontonoz, P. Long noncoding RNA discovery in cardiovascular disease: decoding form to function. Circ. Res. 122, 155–166 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. Carrion, K. et al. The long non-coding HOTAIR is modulated by cyclic stretch and WNT/beta-CATENIN in human aortic valve cells and is a novel repressor of calcification genes. PLOS ONE 9, e96577 (2014).

    PubMed  PubMed Central  Google Scholar 

  269. Yang, J. H. & Saucerman, J. J. Computational models reduce complexity and accelerate insight into cardiac signaling networks. Circ. Res. 108, 85–97 (2011).

    PubMed  PubMed Central  Google Scholar 

  270. Noble, D. Modeling the heart—from genes to cells to the whole organ. Science 295, 1678–1682 (2002).

    CAS  PubMed  Google Scholar 

  271. Huxley, A. F. Muscle structure and theories of contraction. Prog. Biophys. Biophys. Chem. 7, 255–318 (1957).

    CAS  PubMed  Google Scholar 

  272. Noble, D. Cardiac action and pacemaker potentials based on the Hodgkin-Huxley equations. Nature 188, 495–497 (1960).

    CAS  PubMed  Google Scholar 

  273. Jafri, M. S., Rice, J. J. & Winslow, R. L. Cardiac Ca2+ dynamics: the roles of ryanodine receptor adaptation and sarcoplasmic reticulum load. Biophys. J. 74, 1149–1168 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Luo, C. H. & Rudy, Y. A dynamic model of the cardiac ventricular action potential. Afterdepolarizations, II. triggered activity, and potentiation. Circ. Res. 74, 1097–1113 (1994).

    CAS  PubMed  Google Scholar 

  275. Cortassa, S., Aon, M. A., Marban, E., Winslow, R. L. & O’Rourke, B. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys. J. 84, 2734–2755 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Beard, D. A. A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation. PLOS Comput. Biol. 1, e36 (2005).

    PubMed  PubMed Central  Google Scholar 

  277. Saucerman, J. J., Brunton, L. L., Michailova, A. P. & McCulloch, A. D. Modeling beta-adrenergic control of cardiac myocyte contractility in silico. J. Biol. Chem. 278, 47997–48003 (2003).

    CAS  PubMed  Google Scholar 

  278. Hund, T. J. & Rudy, Y. Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model. Circulation 110, 3168–3174 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Winslow, R. L., Rice, J., Jafri, S., Marban, E. & O’Rourke, B. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: model studies. Circ. Res. 84, 571–586 (1999).

    CAS  PubMed  Google Scholar 

  280. Kang, J. H., Lee, H. S., Kang, Y. W. & Cho, K. H. Systems biological approaches to the cardiac signaling network. Brief Bioinform. 17, 419–428 (2016).

    CAS  PubMed  Google Scholar 

  281. Tavi, P. et al. Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression. J. Physiol. 554, 309–320 (2004).

    CAS  PubMed  Google Scholar 

  282. Berridge, M. J., Bootman, M. D. & Roderick, H. L. Calcium signalling: dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 4, 517–529 (2003).

    CAS  PubMed  Google Scholar 

  283. Colella, M. et al. Ca2+ oscillation frequency decoding in cardiac cell hypertrophy: role of calcineurin/NFAT as Ca2+ signal integrators. Proc. Natl Acad. Sci. USA 105, 2859–2864 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  284. Saucerman, J. J. & Bers, D. M. Calmodulin mediates differential sensitivity of CaMKII and calcineurin to local Ca2+ in cardiac myocytes. Biophys. J. 95, 4597–4612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Cooling, M. T., Hunter, P. & Crampin, E. J. Sensitivity of NFAT cycling to cytosolic calcium concentration: implications for hypertrophic signals in cardiac myocytes. Biophys. J. 96, 2095–2104 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  286. Cooling, M., Hunter, P. & Crampin, E. J. Modeling hypertrophic IP3 transients in the cardiac myocyte. Biophys. J. 93, 3421–3433 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Shin, S. Y., Yang, H. W., Kim, J. R., Heo, W. D. & Cho, K. H. A hidden incoherent switch regulates RCAN1 in the calcineurin-NFAT signaling network. J. Cell Sci. 124, 82–90 (2011).

    CAS  PubMed  Google Scholar 

  288. Ryall, K. A. et al. Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling. J. Biol. Chem. 287, 42259–42268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Molkentin, J. D. & Robbins, J. With great power comes great responsibility: using mouse genetics to study cardiac hypertrophy and failure. J. Mol. Cell. Cardiol. 46, 130–136 (2009).

    CAS  PubMed  Google Scholar 

  290. Cook, S. A., Clerk, A. & Sugden, P. H. Are transgenic mice the ‘alkahest’ to understanding myocardial hypertrophy and failure? J. Mol. Cell. Cardiol. 46, 118–129 (2009).

    CAS  PubMed  Google Scholar 

  291. Frank, D. U., Sutcliffe, M. D. & Saucerman, J. J. Network-based predictions of in vivo cardiac hypertrophy. J. Mol. Cell. Cardiol. 121, 180–189 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  292. Cheng, B. et al. Cellular mechanosensing of the biophysical microenvironment: A review of mathematical models of biophysical regulation of cell responses. Phys. Life Rev. 22–23, 88–119 (2017).

    PubMed  PubMed Central  Google Scholar 

  293. Novak, I. L., Slepchenko, B. M., Mogilner, A. & Loew, L. M. Cooperativity between cell contractility and adhesion. Phys. Rev. Lett. 93, 268109 (2004).

    PubMed  Google Scholar 

  294. Deshpande, V. S., McMeeking, R. M. & Evans, A. G. A bio-chemo-mechanical model for cell contractility. Proc. Natl Acad. Sci. USA 103, 14015–14020 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  295. Chen, K. et al. Role of boundary conditions in determining cell alignment in response to stretch. Proc. Natl Acad. Sci. USA 115, 986–991 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  296. Grosberg, A. et al. Self-organization of muscle cell structure and function. PLOS Comput. Biol. 7, e1001088 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  297. Livne, A. & Geiger, B. The inner workings of stress fibers - from contractile machinery to focal adhesions and back. J. Cell Sci. 129, 1293–1304 (2016).

    CAS  PubMed  Google Scholar 

  298. Yuan, H., Marzban, B. & Kit Parker, K. Myofibrils in cardiomyocytes tend to assemble along the maximal principle stress directions. J. Biomech. Eng. 139, 121010 (2017).

    Google Scholar 

  299. McCain, M. L., Lee, H., Aratyn-Schaus, Y., Kleber, A. G. & Parker, K. K. Cooperative coupling of cell-matrix and cell-cell adhesions in cardiac muscle. Proc. Natl Acad. Sci. USA 109, 9881–9886 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  300. Lee, L. C., Kassab, G. S. & Guccione, J. M. Mathematical modeling of cardiac growth and remodeling. Wiley Interdiscip. Rev. Syst. Biol. Med. 8, 211–226 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  301. Dingal, P. C. & Discher, D. E. Systems mechanobiology: tension-inhibited protein turnover is sufficient to physically control gene circuits. Biophys. J. 107, 2734–2743 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Sharp, W. W., Terracio, L., Borg, T. K. & Samarel, A. M. Contractile activity modulates actin synthesis and turnover in cultured neonatal rat heart cells. Circ. Res. 73, 172–183 (1993).

    CAS  PubMed  Google Scholar 

  303. Schroer, A. K., Ryzhova, L. M. & Merryman, W. D. Network modeling approach to predict myofibroblast differentiation. Cell. Mol. Bioengineer. 7, 446–459 (2014).

    CAS  Google Scholar 

  304. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    CAS  PubMed  Google Scholar 

  305. Sun, M., Spill, F. & Zaman, M. H. A. Computational model of YAP/TAZ mechanosensing. Biophys. J. 110, 2540–2550 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. Yang, X. et al. LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nat. Cell Biol. 6, 609–617 (2004).

    CAS  PubMed  Google Scholar 

  307. Zeigler, A. C., Richardson, W. J., Holmes, J. W. & Saucerman, J. J. A computational model of cardiac fibroblast signaling predicts context-dependent drivers of myofibroblast differentiation. J. Mol. Cell. Cardiol. 94, 72–81 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  308. Khalil, H. et al. Fibroblast-specific TGF-beta-Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Invest. 127, 3770–3783 (2017).

    PubMed  PubMed Central  Google Scholar 

  309. Tan, P. M., Buchholz, K. S., Omens, J. H., McCulloch, A. D. & Saucerman, J. J. Predictive model identifies key network regulators of cardiomyocyte mechano-signaling. PLOS Comput. Biol. 13, e1005854 (2017).

    PubMed  PubMed Central  Google Scholar 

  310. Lu, H. I. et al. Entresto therapy effectively protects heart and lung against transverse aortic constriction induced cardiopulmonary syndrome injury in rat. Am. J. Transl Res. 10, 2290–2305 (2018).

    PubMed  PubMed Central  Google Scholar 

  311. von Lueder, T. G. et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ. Heart Fail. 8, 71–78 (2015).

    Google Scholar 

  312. Suematsu, Y. et al. LCZ696 (Sacubitril/Valsartan), an angiotensin-receptor neprilysin inhibitor, attenuates cardiac hypertrophy, fibrosis, and vasculopathy in a rat model of chronic kidney disease. J. Card. Fail. 24, 266–275 (2018).

    CAS  PubMed  Google Scholar 

  313. Ambrosi, D. et al. Perspectives on biological growth and remodeling. J. Mech. Phys. Solids 59, 863–883 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  314. Witzenburg, C. M. & Holmes, J. W. A. Comparison of phenomenologic growth laws for myocardial hypertrophy. J. Elast. 129, 257–281 (2017).

    PubMed  PubMed Central  Google Scholar 

  315. Kerckhoffs, R. C., Omens, J. & McCulloch, A. D. A single strain-based growth law predicts concentric and eccentric cardiac growth during pressure and volume overload. Mech. Res. Commun. 42, 40–50 (2012).

    PubMed  Google Scholar 

  316. Young, A. A., Orr, R., Smaill, B. H. & Dell’Italia, L. J. Three-dimensional changes in left and right ventricular geometry in chronic mitral regurgitation. Am. J. Physiol. 271, H2689–H2700 (1996).

    CAS  PubMed  Google Scholar 

  317. Nagatomo, Y. et al. Translational mechanisms accelerate the rate of protein synthesis during canine pressure-overload hypertrophy. Am. J. Physiol. 277, H2176–H2184 (1999).

    CAS  PubMed  Google Scholar 

  318. Rouillard, A. D. & Holmes, J. W. Coupled agent-based and finite-element models for predicting scar structure following myocardial infarction. Prog. Biophys. Mol. Biol. 115, 235–243 (2014).

    PubMed  Google Scholar 

  319. Yamamoto, K. et al. Regulation of cardiomyocyte mechanotransduction by the cardiac cycle. Circulation 103, 1459–1464 (2001).

    CAS  PubMed  Google Scholar 

  320. Russell, B., Curtis, M. W., Koshman, Y. E. & Samarel, A. M. Mechanical stress-induced sarcomere assembly for cardiac muscle growth in length and width. J. Mol. Cell. Cardiol. 48, 817–823 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  321. DrugMonkey. Generalization, not “reproducibility”. Scientopia http://drugmonkey.scientopia.org/2018/02/26/generalization-not-reproducibility/ (2018).

  322. Boerma, M. et al. Microarray analysis of gene expression profiles of cardiac myocytes and fibroblasts after mechanical stress, ionising or ultraviolet radiation. BMC Genomics 6, 6 (2005).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the following funding sources: US National Science Foundation grant 1252854 (J.J.S.); NIH grants R01 HL137755 (J.J.S.), R01 HL137100 (A.D.M.) and U01 HL127564; and US Department of Defense PR 150090 (supporting J.H.O.).

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Nature Reviews Cardiology thanks P. Kohl and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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  1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA

    Jeffrey J. Saucerman & Philip M. Tan

  2. Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA

    Kyle S. Buchholz, Andrew D. McCulloch & Jeffrey H. Omens

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All the authors researched data for the article, discussed its contents and reviewed and edited the manuscript before submission. J.J.S., A.D.M. and J.H.O. wrote the manuscript.

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A.D.M. and J.H.O. are co-founders of and have an equity interest in Insilicomed, and A.D.M. has an equity interest in Vektor Medical. A.D.M. and J.H.O. serve on the scientific advisory board of Insilicomed, and A.D.M. is a scientific adviser to both companies. Some of their research grants have been identified for conflict of interest management on the basis of the overall scope of the project and its potential benefit to these companies. The authors are required to disclose this relationship in publications acknowledging the grant support; however, the research subject and findings reported in this Review did not involve the companies in any way and have no specific relationship with the business activities or scientific interests of either company. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. J.J.S., P.M.T. and K.S.B. declare no competing interests.

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Saucerman, J.J., Tan, P.M., Buchholz, K.S. et al. Mechanical regulation of gene expression in cardiac myocytes and fibroblasts. Nat Rev Cardiol 16, 361–378 (2019). https://doi.org/10.1038/s41569-019-0155-8

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