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Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth

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Abstract

Ability of the heart to undergo pathological or physiological hypertrophy upon increased wall stress is critical for long-term compensatory function in response to increased workload demand. While substantial information has been published on the nature of the fundamental molecular signaling involved in hypertrophy, the role of extracellular matrix protein Fibronectin (Fn) in hypertrophic signaling is unclear. The objective of the study was to delineate the role of Fn during pressure overload-induced pathological cardiac hypertrophy and physiological growth prompted by exercise. Genetic conditional ablation of Fn in adulthood blunts cardiomyocyte hypertrophy upon pressure overload via attenuated activation of nuclear factor of activated T cells (NFAT). Loss of Fn delays development of heart failure and improves survival. In contrast, genetic deletion of Fn has no impact on physiological cardiac growth induced by voluntary wheel running. Down-regulation of the transcription factor c/EBPβ (Ccaat-enhanced binding protein β), which is essential for induction of the physiological growth program, is unaffected by Fn deletion. Nuclear NFAT translocation is triggered by Fn in conjunction with up-regulation of the fetal gene program and hypertrophy of cardiomyocytes in vitro. Furthermore, activation of the physiological gene program induced by insulin stimulation in vitro is attenuated by Fn, whereas insulin had no impact on Fn-induced pathological growth program. Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via NFAT activation. Fn is dispensable for physiological growth in vivo, and Fn attenuates the activation of the physiological growth program in vitro.

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References

  1. Arslan F, Smeets MB, Riem Vis PW, Karper JC, Quax PH, Bongartz LG, Peters JH, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DP (2011) Lack of fibronectin-EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction. Circ Res 108:582–592. doi:10.1161/CIRCRESAHA.110.224428

    Article  PubMed  CAS  Google Scholar 

  2. Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, Shelton JM, Gerard RD, Rothermel BA, Gillette TG, Lavandero S, Hill JA (2012) Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 122:1109–1118. doi:10.1172/JCI60329

    Article  PubMed  CAS  Google Scholar 

  3. Booth AJ, Wood SC, Cornett AM, Dreffs AA, Lu G, Muro AF, White ES, Bishop DK (2012) Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis. J Pathol 226:609–618. doi:10.1002/path.3010

    Article  PubMed  CAS  Google Scholar 

  4. Bostrom P, Mann N, Wu J, Quintero PA, Plovie ER, Panakova D, Gupta RK, Xiao C, MacRae CA, Rosenzweig A, Spiegelman BM (2010) C/EBPbeta controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143:1072–1083. doi:10.1016/j.cell.2010.11.036

    Article  PubMed  Google Scholar 

  5. Carraway MS, Suliman HB, Jones WS, Chen CW, Babiker A, Piantadosi CA (2010) Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart. Circ Res 106:1722–1730. doi:10.1161/CIRCRESAHA.109.214353

    Article  PubMed  CAS  Google Scholar 

  6. Chen H, Huang XN, Yan W, Chen K, Guo L, Tummalapali L, Dedhar S, St-Arnaud R, Wu C, Sepulveda JL (2005) Role of the integrin-linked kinase/PINCH1/alpha-parvin complex in cardiac myocyte hypertrophy. Lab Invest 85:1342–1356. doi:10.1038/labinvest.3700345

    Article  PubMed  CAS  Google Scholar 

  7. Crawford DC, Chobanian AV, Brecher P (1994) Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res 74:727–739. doi:10.1161/01RES.74.4.727

    Article  PubMed  CAS  Google Scholar 

  8. Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG (2010) The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48:504–511. doi:10.1016/j.yjmcc.2009.07.015

    Article  PubMed  CAS  Google Scholar 

  9. Finsen AV, Lunde IG, Sjaastad I, Ostli EK, Lyngra M, Jarstadmarken HO, Hasic A, Nygard S, Wilcox-Adelman SA, Goetinck PF, Lyberg T, Skrbic B, Florholmen G, Tonnessen T, Louch WE, Djurovic S, Carlson CR, Christensen G (2011) Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway. PLoS One 6:e28302. doi:10.1371/journal.pone.0028302

    Article  PubMed  CAS  Google Scholar 

  10. Frangogiannis NG (2011) Matricellular proteins in cardiac adaptation and disease. Phys Rev 92:635–688. doi:10.1152/physrev.00008.2011

    Google Scholar 

  11. Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589. doi:10.1161/01.CIR.0000120390.68287.BB

    Article  PubMed  Google Scholar 

  12. Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79. doi:10.1146/annurev.physiol.65.092101.142243

    Article  PubMed  CAS  Google Scholar 

  13. Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D (2009) Cardiac fibroblasts regulate myocardial proliferation through β1 integrin signaling. Dev Cell 16:233–244. doi:10.1016/j.devcel.2008.12.007

    Article  PubMed  CAS  Google Scholar 

  14. Knowlton AA, Connelly CM, Romo GM, Mamuya W, Apstein CS, Brecher P (1992) Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion. J Clin Invest 89:1060–1068. doi:10.1172/JCI115685

    Article  PubMed  CAS  Google Scholar 

  15. Koitabashi N, Bedja D, Zaiman AL, Pinto YM, Zhang M, Gabrielson KL, Takimoto E, Kass DA (2009) Avoidance of transient cardiomyopathy in cardiomyocyte-targeted tamoxifen-induced MerCreMer gene deletion models. Circ Res 105:12–15. doi:10.1161/CIRCRESAHA.109.198416

    Article  PubMed  CAS  Google Scholar 

  16. Konstandin MH, Toko H, Gastelum GM, Quijada PJ, De La Torre A, Quintana M, Collins B, Din S, Avitabile D, Volkers MJ, Gude NA, Fassler R, Sussman MA (2013) Fibronectin is essential for reparative cardiac progenitor cell response following myocardial infarction. Circ Res 113:115–125. doi:10.1161/CIRCRESAHA.113.301152

    Article  PubMed  CAS  Google Scholar 

  17. Leipner C, Grun K, Muller A, Buchdunger E, Borsi L, Kosmehl H, Berndt A, Janik T, Uecker A, Kiehntopf M, Bohmer FD (2008) Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis. Cardiovasc Res 79:118–126. doi:10.1093/cvr/cvn063

    Article  PubMed  CAS  Google Scholar 

  18. Leiss M, Beckmann K, Giros A, Costell M, Fassler R (2008) The role of integrin binding sites in fibronectin matrix assembly in vivo. Curr Opin Cell Biol 20:502–507. doi:10.1016/j.ceb.2008.06.001

    Article  PubMed  CAS  Google Scholar 

  19. Li L, Muhlfeld C, Niemann B, Pan R, Li R, Hilfiker-Kleiner D, Chen Y, Rohrbach S (2011) Mitochondrial biogenesis and PGC-1 alpha deacetylation by chronic treadmill exercise: differential response in cardiac and skeletal muscle. Bas Res Cardiol 106:1221–1234. doi:10.1007/s00395-011-0213-9

    Article  CAS  Google Scholar 

  20. Lu J, Bian ZY, Zhang R, Zhang Y, Liu C, Yan L, Zhang SM, Jiang DS, Wei X, Zhu XH, Chen M, Wang AB, Chen Y, Yang Q, Liu PP, Li H (2013) Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Bas Res Cardiol 108:326. doi:10.1007/s00395-012-0326-9

    Article  Google Scholar 

  21. MacDonnell SM, Weisser-Thomas J, Kubo H, Hanscome M, Liu Q, Jaleel N, Berretta R, Chen X, Brown JH, Sabri AK, Molkentin JD, Houser SR (2009) CaMKII negatively regulates calcineurin-NFAT signaling in cardiac myocytes. Circ Res 105:316–325. doi:10.1161/CIRCRESAHA.109.194035

    Article  PubMed  CAS  Google Scholar 

  22. Maillet M, van Berlo JH, Molkentin JD (2013) Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14:38–48. doi:10.1038/nrm3495

    Article  PubMed  CAS  Google Scholar 

  23. McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T, Buerger A, Izumo S, Jay PY, Jennings GL (2007) Protective effects of exercise and phosphoinositide 3-kinase (p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104:612–617. doi:10.1073/pnas.0606663104

    Article  PubMed  CAS  Google Scholar 

  24. Munoz R, Moreno M, Oliva C, Orbenes C, Larrain J (2006) Syndecan-4 regulates non-canonical Wnt signalling and is essential for convergent and extension movements in Xenopus embryos. Nat Cell Biol 8:492–500. doi:10.1038/ncb1399

    Article  PubMed  CAS  Google Scholar 

  25. Muraski JA, Rota M, Misao Y, Fransioli J, Cottage C, Gude N, Esposito G, Delucchi F, Arcarese M, Alvarez R, Siddiqi S, Emmanuel GN, Wu W, Fischer K, Martindale JJ, Glembotski CC, Leri A, Kajstura J, Magnuson N, Berns A, Beretta RM, Houser SR, Schaefer EM, Anversa P, Sussman MA (2007) Pim-1 regulates cardiomyocyte survival downstream of Akt. Nat Med 13:1467–1475. doi:10.1038/nm1671

    Article  PubMed  CAS  Google Scholar 

  26. Nadu AP, Ferreira AJ, Reudelhuber TL, Bader M, Santos RA (2008) Reduced isoproterenol-induced renin-angiotensin changes and extracellular matrix deposition in hearts of TGR (A1-7)3292 rats. J Am Soc Hypertens 2:341–348. doi:10.1016/j.jash.2008.04.012

    Article  PubMed  Google Scholar 

  27. Ogawa E, Saito Y, Harada M, Kamitani S, Kuwahara K, Miyamoto Y, Ishikawa M, Hamanaka I, Kajiyama N, Takahashi N, Nakagawa O, Masuda I, Kishimoto I, Nakao K (2000) Outside-in signalling of fibronectin stimulates cardiomyocyte hypertrophy in cultured neonatal rat ventricular myocytes. J Mol Cell Cardiol 32:765–776. doi:10.1006/jmcc.2000.1119

    Article  PubMed  CAS  Google Scholar 

  28. Oh M, Dey A, Gerard RD, Hill JA, Rothermel BA (2010) The CCAAT/enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4. J Biol Chem 285:16623–16631. doi:10.1074/jbc.M109.098236

    Article  PubMed  CAS  Google Scholar 

  29. Oliver N, Babu M, Diegelmann R (1992) Fibronectin gene transcription is enhanced in abnormal wound healing. J Inv Dermatol 99:579–586. doi:10.1111/1523-1747.ep12667776

    Article  CAS  Google Scholar 

  30. Piepoli MF, Conraads V, Corra U, Dickstein K, Francis DP, Jaarsma T, McMurray J, Pieske B, Piotrowicz E, Schmid JP, Anker SD, Solal AC, Filippatos GS, Hoes AW, Gielen S, Giannuzzi P, Ponikowski PP (2011) Exercise training in heart failure: from theory to practice. A consensus document of the heart failure association and the European association for cardiovascular prevention and rehabilitation. Eur J Heart Fail 13:347–357. doi:10.1093/eurjhf/hfr017

    Article  PubMed  Google Scholar 

  31. Plante E, Lachance D, Gaudreau M, Drolet MC, Roussel E, Arsenault M, Couet J (2004) Effectiveness of beta-blockade in experimental chronic aortic regurgitation. Circulation 110:1477–1483. doi:10.1161/01.CIR.0000141733.55236.9D

    Article  PubMed  CAS  Google Scholar 

  32. Reilly JT, McVerry BA, Mackie MJ (1983) Fibronectin in blood products-an in vitro and in vivo study. J Clin Pathol 36:1377–1381. doi:10.1136/jcp.36.12.1377

    Article  PubMed  CAS  Google Scholar 

  33. Rohwedder I, Montanez E, Beckmann K, Bengtsson E, Duner P, Nilsson J, Soehnlein O, Fassler R (2012) Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation. EMBO Mol Med 4:564–576. doi:10.1002/emmm.201200237

    Article  PubMed  CAS  Google Scholar 

  34. Roof SR, Tang L, Ostler JE, Periasamy M, Gyorke S, Billman GE, Ziolo MT (2013) Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise. Bas Res Cardiol 108:332. doi:10.1007/s00395-013-0332-6

    Article  Google Scholar 

  35. Sakai T, Johnson KJ, Murozono M, Sakai K, Magnuson MA, Wieloch T, Cronberg T, Isshiki A, Erickson HP, Fassler R (2001) Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med 7:324–330. doi:10.1038/85471

    Article  PubMed  CAS  Google Scholar 

  36. Samuel JL, Barrieux A, Dufour S, Dubus I, Contard F, Koteliansky V, Farhadian F, Marotte F, Thiery JP, Rappaport L (1991) Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload. J Clin Invest 88:1737–1746. doi:10.1172/JCI115492

    Article  PubMed  CAS  Google Scholar 

  37. Sharma S, Quintana A, Findlay GM, Mettlen M, Baust B, Jain M, Nilsson R, Rao A, Hogan PG (2013) An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca entry. Nature 499:238–242. doi:10.1038/nature12229

    Article  PubMed  CAS  Google Scholar 

  38. Spinale FG (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Phys Rev 87:1285–1342. doi:10.1152/physrev.00012.2007

    Article  CAS  Google Scholar 

  39. Taylor JM, Rovin JD, Parsons JT (2000) A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem 275:19250–19257. doi:10.1074/jbc.M909099199

    Article  PubMed  CAS  Google Scholar 

  40. van Berlo JH, Maillet M, Molkentin JD (2013) Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest 123:37–45. doi:10.1172/JCI62839

    Article  PubMed  Google Scholar 

  41. van Rooij E, Doevendans PA, de Theije CC, Babiker FA, Molkentin JD, de Windt LJ (2002) Requirement of nuclear factor of activated T-cells in calcineurin-mediated cardiomyocyte hypertrophy. J Biol Chem 277:48617–48626. doi:10.1074/jbc.M206532200

    Article  PubMed  Google Scholar 

  42. Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH (1993) Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88:2849–2861. doi:10.1161/01.CIR.88.6.2849

    Article  PubMed  CAS  Google Scholar 

  43. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118. doi:10.1161/01.RES.0000109415.17511.18

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants of the National Institute of Health to M. Sussman (R01HL067245, R01HL105759, R01HL113656, R21HL102613, R21HL104544, R21HL102714, R37HL091102, RC1HL100891), and to M. Quintana (SDSU MARC 5T34GM008303-23), by a pre-doctoral fellowship of the American Heart Association to S. Din (12PRE12060248) and the Deutsche Forschungsgemeinschaft DFG (1659/1-1 to M. Völkers and 3900/1-1 to M. Konstandin). We would like to thank Prof. Dr. Reinhard Fässler for generously providing Fnfl/fl mice.

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Authors and Affiliations

  1. Heart Institute, and Biology Department, SDSU Integrated Regenerative Research Institute, Life Sciences North, Room 426, 5500 Campanile Drive, San Diego, CA, 92182, USA

    Mathias H. Konstandin, Mirko Völkers, Brett Collins, Pearl Quijada, Mercedes Quintana, Andrea De La Torre, Lucy Ormachea, Shabana Din, Natalie Gude, Haruhiro Toko & Mark A. Sussman

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  1. Mathias H. Konstandin
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  2. Mirko Völkers
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Correspondence to Mark A. Sussman.

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Konstandin, M.H., Völkers, M., Collins, B. et al. Fibronectin contributes to pathological cardiac hypertrophy but not physiological growth. Basic Res Cardiol 108, 375 (2013). https://doi.org/10.1007/s00395-013-0375-8

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