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Melusin, a muscle-specific integrin β1–interacting protein, is required to prevent cardiac failure in response to chronic pressure overload

Nature Medicine volume 9, pages 68–75 (2003)Cite this article

Abstract

Cardiac hypertrophy is an adaptive response to a variety of mechanical and hormonal stimuli, and represents an early event in the clinical course leading to heart failure. By gene inactivation, we demonstrate here a crucial role of melusin, a muscle-specific protein that interacts with the integrin β1 cytoplasmic domain, in the hypertrophic response to mechanical overload. Melusin-null mice showed normal cardiac structure and function in physiological conditions, but when subjected to pressure overload—a condition that induces a hypertrophic response in wild-type controls—they developed an abnormal cardiac remodeling that evolved into dilated cardiomyopathy and contractile dysfunction. In contrast, the hypertrophic response was identical in wild-type and melusin-null mice after chronic administration of angiotensin II or phenylephrine at doses that do not increase blood pressure—that is, in the absence of cardiac biomechanical stress. Analysis of intracellular signaling events induced by pressure overload indicated that phosphorylation of glycogen synthase kinase-3β (GSK-3β) was specifically blunted in melusin-null hearts. Thus, melusin prevents cardiac dilation during chronic pressure overload by specifically sensing mechanical stress.

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Figure 1: Targeted disruption of the mouse melusin gene.
Figure 2: Left ventricle growth response 1 wk after TAC.
Figure 3: Left ventricle remodeling and function 2 and 4 wk after TAC.
Figure 4: Left ventricle hypertrophic growth response to sub-pressor doses of angiotensin II or phenylephrine.
Figure 5: Impaired GSK3-β phosphorylation in melusin-null mice in response to TAC.

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References

  1. Chien, K.R. Stress pathways and heart failure. Cell 98, 555–558 (1999).

    Article  CAS  Google Scholar 

  2. Chien, K.R. & Olson, E.N. Converging pathways and principles in heart development and disease: CV@CSH. Cell 110, 153–162 (2002).

    Article  CAS  Google Scholar 

  3. Sadoshima, J. & Izumo, S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu. Rev. Physiol. 59, 551–571 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Schultz Jel, J. et al. TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J. Clin. Invest. 109, 787–796 (2002).

    Article  Google Scholar 

  7. MacLellan, W.R. & Schneider, M.D. Genetic dissection of cardiac growth control pathways. Annu. Rev. Physiol. 62, 289–319 (2000).

    Article  CAS  Google Scholar 

  8. Yamazaki, T. et al. Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy. J. Biol. Chem. 271, 3221–3228 (1996).

    Article  CAS  Google Scholar 

  9. Wettschureck, N. et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/Gα11 in cardiomyocytes. Nat. Med. 7, 1236–1240 (2001).

    Article  CAS  Google Scholar 

  10. Akhter, S.A. et al. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science 280, 574–577 (1998).

    Article  CAS  Google Scholar 

  11. Dorn, G.W. 2nd & Brown, J.H. Gq signaling in cardiac adaptation and maladaptation. Trends Cardiovasc. Med. 9, 26–34 (1999).

    Article  CAS  Google Scholar 

  12. Wakasaki, H. et al. Targeted overexpression of protein kinase C β2 isoform in myocardium causes cardiomyopathy. Proc. Natl. Acad. Sci. USA 94, 9320–9325 (1997).

    Article  CAS  Google Scholar 

  13. Sugden, P.H. & Clerk, A. Cellular mechanisms of cardiac hypertrophy. J. Mol. Med. 76, 725–746 (1998).

    Article  CAS  Google Scholar 

  14. Hunter, J.J. & Chien, K.R. Signaling pathways for cardiac hypertrophy and failure. N. Engl. J. Med. 341, 1276–1283 (1999).

    Article  CAS  Google Scholar 

  15. Harada, K. et al. Pressure overload induces cardiac hypertrophy in angiotensin II type 1A receptor knockout mice. Circulation 97, 1952–1959 (1998).

    Article  CAS  Google Scholar 

  16. Vecchione, C. et al. Cardiovascular influences of α1b-adrenergic receptor defect in mice. Circulation 105, 1700–1707 (2002).

    Article  CAS  Google Scholar 

  17. Schwartz, M.A., Schaller, M.D. & Ginsberg, M.H. Integrins: emerging paradigms of signal transduction. Annu. Rev. Cell Dev. Biol. 11, 549–599 (1995).

    Article  CAS  Google Scholar 

  18. Fassler, R. et al. Differentiation and integrity of cardiac muscle cells are impaired in the absence of β1 integrin. J. Cell Sci. 109, 2989–2899 (1996).

    PubMed  Google Scholar 

  19. Keller, R.S. et al. Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance. Am. J. Pathol. 158, 1079–1090 (2001).

    Article  CAS  Google Scholar 

  20. Shai, S.Y. et al. Cardiac myocyte-specific excision of the β1 integrin gene results in myocardial fibrosis and cardiac failure. Circ. Res. 90, 458–464 (2002).

    Article  CAS  Google Scholar 

  21. Brancaccio, M. et al. Melusin is a new muscle-specific interactor for β1 integrin cytoplasmic domain. J. Biol. Chem. 274, 29282–29288 (1999).

    Article  CAS  Google Scholar 

  22. Hirota, H. et al. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97, 189–198 (1999).

    Article  CAS  Google Scholar 

  23. Badorff, C. et al. Fas receptor signaling inhibits glycogen synthase kinase 3β and induces cardiac hypertrophy following pressure overload. J. Clin. Invest. 109, 373–381 (2002).

    Article  CAS  Google Scholar 

  24. Rockman, H.A., Koch, W.J. & Lefkowitz, R.J. Seven-transmembrane-spanning receptors and heart function. Nature 415, 206–212 (2002).

    Article  CAS  Google Scholar 

  25. Haq, S. et al. Glycogen synthase kinase-3β is a negative regulator of cardiomyocyte hypertrophy. J. Cell Biol. 151, 117–130 (2000).

    Article  CAS  Google Scholar 

  26. Morisco, C. et al. Glycogen synthase kinase 3β regulates GATA4 in cardiac myocytes. J. Biol. Chem. 276, 28586–28597 (2001).

    Article  CAS  Google Scholar 

  27. Antos, C.L. et al. Activated glycogen synthase-3β suppresses cardiac hypertrophy in vivo. Proc. Natl. Acad. Sci. USA 99, 907–912 (2002).

    Article  CAS  Google Scholar 

  28. Cohen, P. & Frame, S. The renaissance of GSK3. Nat. Rev. Mol. Cell Biol. 2, 769–776 (2001).

    Article  CAS  Google Scholar 

  29. Persad, S. et al. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem. 276, 27462–27469 (2001).

    Article  CAS  Google Scholar 

  30. Ivaska, J. et al. Integrin α2β1 mediates isoform-specific activation of p38 and upregulation of collagen gene transcription by a mechanism involving the α2 cytoplasmic tail. J. Cell Biol. 147, 401–416 (1999).

    Article  CAS  Google Scholar 

  31. Norton, G.R. et al. Heart failure in pressure overload hypertrophy. The relative roles of ventricular remodeling and myocardial dysfunction. J. Am. Coll. Cardiol. 39, 664–671 (2002).

    Article  Google Scholar 

  32. Esposito, G. et al. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105, 85–92 (2002).

    Article  CAS  Google Scholar 

  33. Wang, Y. Signal transduction in cardiac hypertrophy—dissecting compensatory versus pathological pathways utilizing a transgenic approach. Curr. Opin. Pharmacol. 1, 134–140 (2001).

    Article  CAS  Google Scholar 

  34. MacLellan, W.R. Advances in the molecular mechanisms of heart failure. Curr. Opin. Cardiol. 15, 128–135 (2000).

    Article  CAS  Google Scholar 

  35. Nicol, R.L. et al. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J. 20, 2757–2767 (2001).

    Article  CAS  Google Scholar 

  36. Wollert, K.C. et al. The cardiac Fas (APO-1/CD95) Receptor/Fas ligand system relation to diastolic wall stress in volume-overload hypertrophy in vivo and activation of the transcription factor AP-1 in cardiac myocytes. Circulation 101, 1172–1178 (2000).

    Article  CAS  Google Scholar 

  37. Schwartz, M.A. & Ginsberg, M.H. Networks and crosstalk: integrin signalling spreads. Nat. Cell Biol. 4, E65–E658 (2002).

    Article  CAS  Google Scholar 

  38. Lembo, G. et al. Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency. J. Clin. Invest. 98, 2648–2655 (1996).

    Article  CAS  Google Scholar 

  39. Belkin, A.M. et al. Muscle β1D integrin reinforces the cytoskeleton-matrix link: modulation of integrin adhesive function by alternative splicing. J. Cell Biol. 139, 1583–1595 (1997).

    Article  CAS  Google Scholar 

  40. Brancaccio, M. et al. Differential onset of expression of α7 and β1D integrins during mouse heart and skeletal muscle development. Cell Adhes. Commun. 5, 193–205 (1998).

    Article  CAS  Google Scholar 

  41. Condorelli, G. et al. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation 99, 3071–3078 (1999).

    Article  CAS  Google Scholar 

  42. Cabodi, S. et al. A PKC-β/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation. Mol. Cell 6, 1121–1129 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank O. Azzolino, I. Carfora and G. Russo for technical assistance; D. Bongioanni, B. Canepa, R. Ferretti and M. Sbroggiò for help with several experiments; V. Poli and S. Cabodi for suggestions and critical reading of the manuscript; and A. Fubini for great enthusiasm and support in the initial analysis of the mouse phenotype. This work was supported by grants from Telethon to G.T., the Ministry of University and Research to G.T. and G.L., the Italian National Research Council to F.A. and E.H., and the Italian Ministry of Health to G.L.

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Author notes

  1. Mara Brancaccio and Luigi Fratta: M.B. and L.F. contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Biology, and Biochemistry, Turin University, Turin, 10126, Italy

    Mara Brancaccio, Emilio Hirsch, Simona Guazzone, Marika De Acetis, Fiorella Altruda, Lorenzo Silengo & Guido Tarone

  2. Department of Angiocardioneurology, IRCCS 'Neuromed', Pozzilli (IS), 86077, Italy

    Luigi Fratta, Antonella Notte, Roberta Poulet, Carmine Vecchione, Gennaro Marino & Giuseppe Lembo

  3. Experimental Medicine Research Center, San Giovanni Battista Hospital, Turin, 10126, Italy

    Emilio Hirsch, Fiorella Altruda, Lorenzo Silengo & Guido Tarone

  4. Department of Experimental Medicine and Pathology, University of Rome 'La Sapienza', Rome, Italy

    Giuseppe Lembo

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  1. Mara Brancaccio
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Correspondence to Guido Tarone or Giuseppe Lembo.

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Brancaccio, M., Fratta, L., Notte, A. et al. Melusin, a muscle-specific integrin β1–interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med 9, 68–75 (2003). https://doi.org/10.1038/nm805

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