Review Article | Published:

Assigning matrix metalloproteinase roles in ischaemic cardiac remodelling

Nature Reviews Cardiologyvolume 15pages471479 (2018) | Download Citation

Abstract

Matrix metalloproteinases (MMPs) and their endogenous inhibitors have been studied in the myocardium for the past 2 decades. An incomplete knowledge base and experimental design issues with inhibitors have hampered attempts at translation, but clinical interest remains high because of strong associations between MMPs and outcomes after myocardial infarction (MI) as well as mechanistic studies showing MMP involvement at multiple stages of the MI wound-healing process. This Review focuses on how our understanding of MMPs has evolved from a one-dimensional early focus on measuring MMP activity, monitoring MMP:inhibitor ratios, and evaluating one MMP–substrate pair to the current use of systems biology approaches to integrate the whole MMP repertoire of roles in the left ventricular response to MI. MMP9 is used as an example MMP to explain these concepts and to provide a template for examining MMPs as mechanistic mediators of cardiac remodelling.

Key points

  • Matrix metalloproteinases (MMPs) are not one-size-fits-all enzymes; MMPs overlap in substrate profiles, but each has a distinct role in cardiac remodelling after myocardial infarction.

  • MMP9 is the most-studied MMP in cardiac remodelling after myocardial infarction.

  • MMP roles are dictated by the substrates they process, and the best way to assess in vivo MMP activity is to show substrate cleavage.

  • The mechanisms by which MMPs interact with each other in the myocardium have not been examined beyond which MMPs compensate for the loss of one MMP and which MMPs serve as upstream activators for other MMPs.

  • This Review provides a template for examining MMPs as mechanistic mediators of cardiac remodelling.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

MEROPS peptidase database: https://www.ebi.ac.uk/merops/

References

  1. 1.

    Frangogiannis, N. G. The inflammatory response in myocardial injury, repair, and remodelling. Nat. Rev. Cardiol. 11, 255–265 (2014).

  2. 2.

    Prabhu, S. D. & Frangogiannis, N. G. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ. Res. 119, 91–112 (2016).

  3. 3.

    Dixon, J. A. & Spinale, F. G. Myocardial remodeling: cellular and extracellular events and targets. Annu. Rev. Physiol. 73, 47–68 (2011).

  4. 4.

    Spinale, F. G. et al. Crossing into the next frontier of cardiac extracellular matrix research. Circ. Res. 119, 1040–1045 (2016).

  5. 5.

    Clarke, S. A., Richardson, W. J. & Holmes, J. W. Modifying the mechanics of healing infarcts: Is better the enemy of good? J. Mol. Cell. Cardiol. 93, 115–124 (2016).

  6. 6.

    DeLeon-Pennell, K. Y., Meschiari, C. A., Jung, M. & Lindsey, M. L. Matrix metalloproteinases in myocardial infarction and heart failure. Prog. Mol. Biol. Transl Sci. 147, 75–100 (2017).

  7. 7.

    Spinale, F. G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285–1342 (2007).

  8. 8.

    Voorhees, A. P. et al. Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction. J. Mol. Cell. Cardiol. 85, 229–239 (2015).

  9. 9.

    Spinale, F. G. & Villarreal, F. Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem. Pharmacol. 90, 7–15 (2014).

  10. 10.

    Spinale, F. G. & Zile, M. R. Integrating the myocardial matrix into heart failure recognition and management. Circ. Res. 113, 725–738 (2013).

  11. 11.

    Iyer, R. P., Jung, M. & Lindsey, M. L. MMP-9 signaling in the left ventricle following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 311, H190–198 (2016).

  12. 12.

    Yabluchanskiy, A., Ma, Y., Iyer, R. P., Hall, M. E. & Lindsey, M. L. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology 28, 391–403 (2013).

  13. 13.

    Lovett, D. H., Chu, C., Wang, G., Ratcliffe, M. B. & Baker, A. J. A. N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium. Front. Physiol. 5, 363 (2014).

  14. 14.

    Lovett, D. H. et al. N-Terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure. PLoS ONE 8, e68154 (2013).

  15. 15.

    Iyer, R. P., Patterson, N. L., Fields, G. B. & Lindsey, M. L. The history of matrix metalloproteinases: milestones, myths, and misperceptions. Am. J. Physiol. Heart Circ. Physiol. 303, H919–H930 (2012).

  16. 16.

    Kleiner, D. E. & Stetler-Stevenson, W. G. Quantitative zymography: detection of picogram quantities of gelatinases. Anal. Biochem. 218, 325–329 (1994).

  17. 17.

    Vandooren, J., Van den Steen, P. E. & Opdenakker, G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit. Rev. Biochem. Mol. Biol. 48, 222–272 (2013).

  18. 18.

    Lindsey, M. et al. Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. Circulation 103, 2181–2187 (2001).

  19. 19.

    Zamilpa, R. et al. Proteomic analysis identifies in vivo candidate matrix metalloproteinase-9 substrates in the left ventricle post-myocardial infarction. Proteomics 10, 2214–2223 (2010).

  20. 20.

    Chiao, Y. A. et al. In vivo matrix metalloproteinase-7 substrates identified in the left ventricle post-myocardial infarction using proteomics. J. Proteome Res. 9, 2649–2657 (2010).

  21. 21.

    Lindsey, M. L. et al. A novel collagen matricryptin reduces left ventricular dilation post-myocardial infarction by promoting scar formation and angiogenesis. J. Am. Coll. Cardiol. 66, 1364–1374 (2015).

  22. 22.

    Iyer, R. P., de Castro Bras, L. E., Jin, Y. F. & Lindsey, M. L. Translating Koch’s postulates to identify matrix metalloproteinase roles in postmyocardial infarction remodeling: cardiac metalloproteinase actions (CarMA) postulates. Circ. Res. 114, 860–871 (2014).

  23. 23.

    Yabluchanskiy, A. et al. Myocardial infarction superimposed on aging: MMP-9 deletion promotes M2 macrophage polarization. J. Gerontol. A Biol. Sci. Med. Sci. 71, 475–483 (2016).

  24. 24.

    Iyer, R. P. et al. Early matrix metalloproteinase-9 inhibition post-myocardial infarction worsens cardiac dysfunction by delaying inflammation resolution. J. Mol. Cell. Cardiol. 100, 109–117 (2016).

  25. 25.

    Meschiari, C. A. et al. Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 314, H224–H235 (2017).

  26. 26.

    DeLeon-Pennell, K. Y. et al. CD36 is a matrix metalloproteinase-9 substrate that stimulates neutrophil apoptosis and removal during cardiac remodeling. Circ. Cardiovasc. Genet. 9, 14–25 (2016).

  27. 27.

    Dai, X., Kaul, P., Smith, S. C. Jr & Stouffer, G. A. Predictors, treatment, and outcomes of STEMI occurring in hospitalized patients. Nat. Rev. Cardiol. 13, 148–154 (2016).

  28. 28.

    Blankenberg, S. et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation 107, 1579–1585 (2003).

  29. 29.

    Ma, Y. et al. Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ. Res. 112, 675–688 (2013).

  30. 30.

    de Castro Bras, L. E. et al. Citrate synthase is a novel in vivo matrix metalloproteinase-9 substrate that regulates mitochondrial function in the postmyocardial infarction left ventricle. Antioxid. Redox Signal. 21, 1974–1985 (2014).

  31. 31.

    Lindsey, M. L., Zouein, F. A., Tian, Y., Padmanabhan Iyer, R. & de Castro Bras, L. E. Osteopontin is proteolytically processed by matrix metalloproteinase 9. Can. J. Physiol. Pharmacol. 93, 879–886 (2015).

  32. 32.

    Takawale, A., Sakamuri, S. S. & Kassiri, Z. Extracellular matrix communication and turnover in cardiac physiology and pathology. Compr. Physiol. 5, 687–719 (2015).

  33. 33.

    Ma, Y. et al. Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence. Cardiovasc. Res. 106, 421–431 (2015).

  34. 34.

    Iyer, R. P. et al. Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution. Int. J. Cardiol. 185, 198–208 (2015).

  35. 35.

    Dehn, S. & Thorp, E. B. Myeloid receptor CD36 is required for early phagocytosis of myocardial infarcts and induction of Nr4a1-dependent mechanisms of cardiac repair. FASEB J. 32, 254–264 (2018).

  36. 36.

    Ricard-Blum, S. & Vallet, S. D. Fragments generated upon extracellular matrix remodeling: biological regulators and potential drugs. Matrix Biol. https://doi.org/10.1016/j.matbio.2017.11.005 (2017).

  37. 37.

    Bouchet, S. & Bauvois, B. Neutrophil gelatinase-associated lipocalin (NGAL), pro-matrix metalloproteinase-9 (pro-MMP-9) and their complex pro-MMP-9/NGAL in leukaemias. Cancers 6, 796–812 (2014).

  38. 38.

    Gharib, S. A., Manicone, A. M. & Parks, W. C. Matrix metalloproteinases in emphysema. Matrix Biol. https://doi.org/10.1016/j.matbio.2018.01.018 (2018).

  39. 39.

    Zamilpa, R. et al. Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction. J. Mol. Cell. Cardiol. 53, 599–608 (2012).

  40. 40.

    Cerisano, G. et al. Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial. Eur. Heart J. 35, 184–191 (2014).

  41. 41.

    Cerisano, G. et al. Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial. Int. J. Cardiol. 197, 147–153 (2015).

  42. 42.

    Lindsey, M. L., Hall, M. E., Harmancey, R. & Ma, Y. Adapting extracellular matrix proteomics for clinical studies on cardiac remodeling post-myocardial infarction. Clin. Proteom. 13, 19 (2016).

  43. 43.

    Lindsey, M. L. et al. Transformative impact of proteomics on cardiovascular health and disease: a scientific statement from the American Heart Association. Circulation 132, 852–872 (2015).

  44. 44.

    Brooks, H. L. & Lindsey, M. L. Guidelines for authors and reviewers on antibody use in physiology studies. Am. J. Physiol. Heart Circ. Physiol. 314, H724–H732 (2018).

  45. 45.

    Lindsey, M. L. et al. Guidelines for experimental models of myocardial ischemia and infarction. Am. J. Physiol. Heart Circ. Physiol. 314, H812–H838 (2018).

  46. 46.

    Lindsey, M. L., Kassiri, Z., Virag, J. A. I., de Castro Bras, L. E. & Scherrer-Crosbie, M. Guidelines for measuring cardiac physiology in mice. Am. J. Physiol. Heart Circ. Physiol. 314, H733–H752 (2018).

  47. 47.

    Buache, E. et al. Functional relationship between matrix metalloproteinase-11 and matrix metalloproteinase-14. Cancer Med. 3, 1197–1210 (2014).

  48. 48.

    Koenig, G. C. et al. MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction. Am. J. Pathol. 180, 1863–1878 (2012).

  49. 49.

    Tobar, N. et al. Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells. Carcinogenesis 35, 1770–1779 (2014).

  50. 50.

    Boon, L., Ugarte-Berzal, E., Vandooren, J. & Opdenakker, G. Glycosylation of matrix metalloproteases and tissue inhibitors: present state, challenges and opportunities. Biochem. J. 473, 1471–1482 (2016).

  51. 51.

    Hulsmans, M. et al. Cardiac macrophages promote diastolic dysfunction. J. Exp. Med. 215, 423–440 (2018).

  52. 52.

    Honold, L. & Nahrendorf, M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ. Res. 122, 113–127 (2018).

  53. 53.

    Hulsmans, M., Sam, F. & Nahrendorf, M. Monocyte and macrophage contributions to cardiac remodeling. J. Mol. Cell. Cardiol. 93, 149–155 (2016).

  54. 54.

    Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).

  55. 55.

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

  56. 56.

    Daniels, L. B. & Maisel, A. S. Cardiovascular biomarkers and sex: the case for women. Nat. Rev. Cardiol. 12, 588–596 (2015).

  57. 57.

    Viereck, J. & Thum, T. Circulating noncoding RNAs as biomarkers of cardiovascular disease and injury. Circ. Res. 120, 381–399 (2017).

  58. 58.

    Schloss, M. J. et al. The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment. EMBO Mol. Med. 8, 937–948 (2016).

  59. 59.

    Anea, C. B. et al. Matrix metalloproteinase 2 and 9 dysfunction underlie vascular stiffness in circadian clock mutant mice. Arterioscler. Thromb. Vasc. Biol. 30, 2535–2543 (2010).

  60. 60.

    Lou, J., Wang, Y., Zhang, Z. & Qiu, W. Activation of MMPs in macrophages by Mycobacterium tuberculosis via the miR-223-BMAL1 signaling pathway. J. Cell. Biochem. 118, 4804–4812 (2017).

  61. 61.

    Kloner, R. A. et al. New and revisited approaches to preserving the reperfused myocardium. Nat. Rev. Cardiol. 14, 679–693 (2017).

  62. 62.

    Meschiari, C. A., Ero, O. K., Pan, H., Finkel, T. & Lindsey, M. L. The impact of aging on cardiac extracellular matrix. Geroscience 39, 7–18 (2017).

  63. 63.

    Van den Steen, P. E. et al. The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition and binding to cargo receptors. J. Biol. Chem. 281, 18626–18637 (2006).

  64. 64.

    O’Sullivan, S., Medina, C., Ledwidge, M., Radomski, M. W. & Gilmer, J. F. Nitric oxide-matrix metaloproteinase-9 interactions: biological and pharmacological significance — NO and MMP-9 interactions. Biochim. Biophys. Acta 1843, 603–617 (2014).

  65. 65.

    El-Aziz, T. A. A. & Mohamed, R. H. Matrix metalloproteinase -9 polymorphism and outcome after acute myocardial infarction. Int. J. Cardiol. 227, 524–528 (2017).

  66. 66.

    Duellman, T., Burnett, J. & Yang, J. Functional roles of N-linked glycosylation of human matrix metalloproteinase 9. Traffic 16, 1108–1126 (2015).

  67. 67.

    Rouet-Benzineb, P., Gontero, B., Dreyfus, P. & Lafuma, C. Angiotensin II induces nuclear factor-κB activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J. Mol. Cell. Cardiol. 32, 1767–1778 (2000).

  68. 68.

    Poggio, P. et al. Osteopontin controls endothelial cell migration in vitro and in excised human valvular tissue from patients with calcific aortic stenosis and controls. J. Cell. Physiol. 226, 2139–2149 (2011).

  69. 69.

    Kothari, P. et al. IL-6-mediated induction of matrix metalloproteinase-9 is modulated by JAK-dependent IL-10 expression in macrophages. J. Immunol. 192, 349–357 (2014).

  70. 70.

    Hartney, J. M., Gustafson, C. E., Bowler, R. P., Pelanda, R. & Torres, R. M. Thromboxane receptor signaling is required for fibronectin-induced matrix metalloproteinase 9 production by human and murine macrophages and is attenuated by the Arhgef1 molecule. J. Biol. Chem. 286, 44521–44531 (2011).

  71. 71.

    Dai, J. et al. Osteopontin induces angiogenesis through activation of PI3K/AKT and ERK1/2 in endothelial cells. Oncogene 28, 3412–3422 (2009).

  72. 72.

    Chakrabarti, S., Zee, J. M. & Patel, K. D. Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release. J. Leukoc. Biol. 79, 214–222 (2006).

  73. 73.

    Chakrabarti, S. & Patel, K. D. Regulation of matrix metalloproteinase-9 release from IL-8-stimulated human neutrophils. J. Leukoc. Biol. 78, 279–288 (2005).

  74. 74.

    Castrillo, A., Joseph, S. B., Marathe, C., Mangelsdorf, D. J. & Tontonoz, P. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J. Biol. Chem. 278, 10443–10449 (2003).

  75. 75.

    Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005).

  76. 76.

    Lindsey, M. L. et al. Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation 113, 2919–2928 (2006).

  77. 77.

    Squire, I. B., Evans, J., Ng, L. L., Loftus, I. M. & Thompson, M. M. Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction. J. Card. Fail. 10, 328–333 (2004).

  78. 78.

    Wagner, D. R. et al. Matrix metalloproteinase-9 is a marker of heart failure after acute myocardial infarction. J. Card. Fail. 12, 66–72 (2006).

  79. 79.

    DeLeon-Pennell, K. Y. et al. P. gingivalis lipopolysaccharide intensifies inflammation post-myocardial infarction through matrix metalloproteinase-9. J. Mol. Cell. Cardiol. 76, 218–226 (2014).

  80. 80.

    Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 (2000).

  81. 81.

    van den Borne, S. W. et al. Increased matrix metalloproteinase-8 and -9 activity in patients with infarct rupture after myocardial infarction. Cardiovasc. Pathol. 18, 37–43 (2009).

  82. 82.

    Romanic, A. M., Burns-Kurtis, C. L., Gout, B., Berrebi-Bertrand, I. & Ohlstein, E. H. Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci. 68, 799–814 (2001).

  83. 83.

    Cleutjens, J. P., Kandala, J. C., Guarda, E., Guntaka, R. V. & Weber, K. T. Regulation of collagen degradation in the rat myocardium after infarction. J. Mol. Cell. Cardiol. 27, 1281–1292 (1995).

  84. 84.

    Etoh, T. et al. Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs. Am. J. Physiol. Heart Circ. Physiol. 281, H987–H994 (2001).

  85. 85.

    Blom, A. S. et al. Cardiac support device modifies left ventricular geometry and myocardial structure after myocardial infarction. Circulation 112, 1274–1283 (2005).

  86. 86.

    Takai, S. et al. Inhibition of matrix metalloproteinase-9 activity by lisinopril after myocardial infarction in hamsters. Eur. J. Pharmacol. 568, 231–233 (2007).

  87. 87.

    Ramirez, T. A. et al. Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects. J. Mol. Cell. Cardiol. 72, 326–335 (2014).

  88. 88.

    Lindsey, M. L. et al. Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 290, H232–H239 (2006).

  89. 89.

    Lindsey, M. L. et al. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation 105, 753–758 (2002).

Download references

Acknowledgements

The author acknowledges O. J. Rivera Gonzalez and A. J. Mouton (University of Mississippi Medical Center, Jackson, MS, USA) for help with fact checking and careful proofreading of the manuscript. She acknowledges funding from the NIH under Award Numbers GM104357, GM114833, GM115428, HL051971, HL075360, and HL129823, and from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development under Award Number 5I01BX000505. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH or the Veterans Administration.

Reviewer information

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

Author information

Affiliations

  1. Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    • Merry L. Lindsey
  2. Research Service,, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA

    • Merry L. Lindsey

Authors

  1. Search for Merry L. Lindsey in:

Competing interests

The author declares no competing interests.

Corresponding author

Correspondence to Merry L. Lindsey.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/s41569-018-0022-z

Further reading