TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation

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Cardiac fibrosis caused by adverse cardiac remodeling following myocardial infarction can eventually lead to heart failure. Although the role of soluble factors such as TGF-β is well studied in cardiac fibrosis following myocardial injury, the physiological role of mechanotransduction is not fully understood. Here, we investigated the molecular mechanism and functional role of TRPV4 mechanotransduction in cardiac fibrosis. TRPV4KO mice, 8 weeks following myocardial infarction (MI), exhibited preserved cardiac function compared to WT mice. Histological analysis demonstrated reduced cardiac fibrosis in TRPV4KO mice. We found that WT CF exhibited hypotonicity-induced calcium influx and extracellular matrix (ECM)-stiffness-dependent differentiation in response to TGF-β1. In contrast, TRPV4KO CF did not display hypotonicity-induced calcium influx and failed to differentiate on high-stiffness ECM gels even in the presence of saturating amounts of TGF-β1. Mechanistically, TRPV4 mediated cardiac fibrotic gene promoter activity and fibroblast differentiation through the activation of the Rho/Rho kinase pathway and the mechanosensitive transcription factor MRTF-A. Our findings suggest that genetic deletion of TRPV4 channels protects heart from adverse cardiac remodeling following MI by modulating Rho/MRTF-A pathway-mediated cardiac fibroblast differentiation and cardiac fibrosis.

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  1. 1.

    Adapala RK, Talasila PK, Bratz IN, Zhang DX, Suzuki M, Meszaros JG, Thodeti CK (2011) PKCalpha mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells. Am J Physiol Heart Circ Physiol 301:H757–H765.

  2. 2.

    Adapala RK, Thoppil RJ, Ghosh K, Cappelli HC, Dudley AC, Paruchuri S, Keshamouni V, Klagsbrun M, Meszaros JG, Chilian WM, Ingber DE, Thodeti CK (2016) Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy. Oncogene 35:314–322.

  3. 3.

    Adapala RK, Thoppil RJ, Luther DJ, Paruchuri S, Meszaros JG, Chilian WM, Thodeti CK (2013) TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J Mol Cell Cardiol 54:45–52.

  4. 4.

    Al Hattab D, Czubryt MP (2017) A primer on current progress in cardiac fibrosis. Can J Physiol Pharmacol 95:1091–1099.

  5. 5.

    Andrei SR, Ghosh M, Sinharoy P, Dey S, Bratz IN, Damron DS (2017) TRPA1 ion channel stimulation enhances cardiomyocyte contractile function via a CaMKII-dependent pathway. Channels (Austin) 11:587–603.

  6. 6.

    Bell RM, Botker HE, Carr RD, Davidson SM, Downey JM, Dutka DP, Heusch G, Ibanez B, Macallister R, Stoppe C, Ovize M, Redington A, Walker JM, Yellon DM (2016) 9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection. Basic Res Cardiol 111:41.

  7. 7.

    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P, American Heart Association Statistics C, Stroke Statistics S (2017) Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 135:e146–e603.

  8. 8.

    Berrout J, Jin M, Mamenko M, Zaika O, Pochynyuk O, O'Neil RG (2012) Function of transient receptor potential cation channel subfamily V member 4 (TRPV4) as a mechanical transducer in flow-sensitive segments of renal collecting duct system. J Biol Chem 287:8782–8791.

  9. 9.

    Burlew BS, Weber KT (2002) Cardiac fibrosis as a cause of diastolic dysfunction. Herz 27:92–98

  10. 10.

    Cappelli HC, Kanugula AK, Adapala RK, Amin V, Sharma P, Midha P, Paruchuri S, Thodeti CK (2019) Mechanosensitive TRPV4 channels stabilize VE-cadherin junctions to regulate tumor vascular integrity and metastasis. Cancer Lett 442:15–20.

  11. 11.

    Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM (2006) Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci USA 103:17985–17990.

  12. 12.

    Curley D, Lavin Plaza B, Shah AM, Botnar RM (2018) Molecular imaging of cardiac remodelling after myocardial infarction. Basic Res Cardiol 113:10.

  13. 13.

    Davis J, Burr AR, Davis GF, Birnbaumer L, Molkentin JD (2012) A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Dev Cell 23:705–715.

  14. 14.

    Du J, Xie J, Zhang Z, Tsujikawa H, Fusco D, Silverman D, Liang B, Yue L (2010) TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ Res 106:992–1003.

  15. 15.

    Earley S, Heppner TJ, Nelson MT, Brayden JE (2005) TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ Res 97:1270–1279.

  16. 16.

    Esnault C, Stewart A, Gualdrini F, East P, Horswell S, Matthews N, Treisman R (2014) Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes Dev 28:943–958.

  17. 17.

    Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15.

  18. 18.

    Fan Z, Guan J (2016) Antifibrotic therapies to control cardiac fibrosis. Biomater Res 20:13.

  19. 19.

    Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE (2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci USA 105:11305–11310.

  20. 20.

    Hall A (2012) Rho family GTPases. Biochem Soc Trans 40:1378–1382.

  21. 21.

    Hall A, Nobes CD (2000) Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond Ser B Biol Sci 355:965–970.

  22. 22.

    Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S (2012) Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 126:2051–2064.

  23. 23.

    Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, Harteneck C, Liedtke W, Hoyer J, Kohler R (2007) Arterial response to shear stress critically depends on endothelial TRPV4 expression. PLoS ONE 2:e827.

  24. 24.

    Harvey PA, Leinwand LA (2011) The cell biology of disease: cellular mechanisms of cardiomyopathy. J Cell Biol 194:355–365.

  25. 25.

    Hinz B (2009) Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep 11:120–126

  26. 26.

    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170:1807–1816.

  27. 27.

    Jones JL, Peana D, Veteto AB, Lambert MD, Nourian Z, Karasseva NG, Hill MA, Lindman BR, Baines CP, Krenz M, Domeier TL (2019) TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress. Cardiovasc Res 115:46–56.

  28. 28.

    Jourdan-Lesaux C, Zhang J, Lindsey ML (2010) Extracellular matrix roles during cardiac repair. Life Sci 87:391–400.

  29. 29.

    Kanugula AK, Adapala RK, Midha P, Cappelli HC, Meszaros JG, Paruchuri S, Chilian WM, Thodeti CK (2019) Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4. FASEB J 33:195–203.

  30. 30.

    Kass DA, Bronzwaer JG, Paulus WJ (2004) What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 94:1533–1542.

  31. 31.

    Kazakov A, Hall RA, Werner C, Meier T, Trouvain A, Rodionycheva S, Nickel A, Lammert F, Maack C, Bohm M, Laufs U (2018) Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress. Basic Res Cardiol 113:42.

  32. 32.

    Kohler R, Heyken WT, Heinau P, Schubert R, Si H, Kacik M, Busch C, Grgic I, Maier T, Hoyer J (2006) Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol 26:1495–1502.

  33. 33.

    Kong P, Christia P, Frangogiannis NG (2014) The pathogenesis of cardiac fibrosis. Cell Mol Life Sci 71:549–574.

  34. 34.

    Kuo JC (2013) Mechanotransduction at focal adhesions: integrating cytoskeletal mechanics in migrating cells. J Cell Mol Med 17:704–712.

  35. 35.

    Kuwahara K, Barrientos T, Pipes GC, Li S, Olson EN (2005) Muscle-specific signaling mechanism that links actin dynamics to serum response factor. Mol Cell Biol 25:3173–3181.

  36. 36.

    Leask A (2010) Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res 106:1675–1680.

  37. 37.

    Lee HP, Stowers R, Chaudhuri O (2019) Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments. Nat Commun 10:529.

  38. 38.

    Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–535.

  39. 39.

    Lighthouse JK, Small EM (2016) Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol 91:52–60.

  40. 40.

    Luther DJ, Thodeti CK, Shamhart PE, Adapala RK, Hodnichak C, Weihrauch D, Bonaldo P, Chilian WM, Meszaros JG (2012) Absence of type VI collagen paradoxically improves cardiac function, structure, and remodeling after myocardial infarction. Circ Res 110:851–856.

  41. 41.

    Ma Y, Iyer RP, Jung M, Czubryt MP, Lindsey ML (2017) Cardiac fibroblast activation post-myocardial infarction: current knowledge gaps. Trends Pharmacol Sci 38:448–458.

  42. 42.

    Mann DL, Bristow MR (2005) Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111:2837–2849.

  43. 43.

    Manso AM, Okada H, Sakamoto FM, Moreno E, Monkley SJ, Li R, Critchley DR, Ross RS (2017) Loss of mouse cardiomyocyte talin-1 and talin-2 leads to beta-1 integrin reduction, costameric instability, and dilated cardiomyopathy. Proc Natl Acad Sci USA 114:E6250–E6259.

  44. 44.

    Marian AJ, Braunwald E (2017) Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 121:749–770.

  45. 45.

    Matthews BD, Thodeti CK, Tytell JD, Mammoto A, Overby DR, Ingber DE (2010) Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb) 2:435–442.

  46. 46.

    Mendoza SA, Fang J, Gutterman DD, Wilcox DA, Bubolz AH, Li R, Suzuki M, Zhang DX (2010) TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress. Am J Physiol Heart Circ Physiol 298:H466–H476.

  47. 47.

    Morine KJ, Paruchuri V, Qiao X, Aronovitz M, Huggins GS, DeNofrio D, Kiernan MS, Karas RH, Kapur NK (2016) Endoglin selectively modulates transient receptor potential channel expression in left and right heart failure. Cardiovasc Pathol 25:478–482.

  48. 48.

    Nielsen SH, Mouton AJ, DeLeon-Pennell KY, Genovese F, Karsdal M, Lindsey ML (2017) Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes. Matrix Biol.

  49. 49.

    Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255–278.

  50. 50.

    Randhawa PK, Jaggi AS (2015) TRPV4 channels: physiological and pathological role in cardiovascular system. Basic Res Cardiol 110:54.

  51. 51.

    Shimizu T, Narang N, Chen P, Yu B, Knapp M, Janardanan J, Blair J, Liao JK (2017) Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction. JCI Insight.

  52. 52.

    Small EM, Thatcher JE, Sutherland LB, Kinoshita H, Gerard RD, Richardson JA, Dimaio JM, Sadek H, Kuwahara K, Olson EN (2010) Myocardin-related transcription factor-a controls myofibroblast activation and fibrosis in response to myocardial infarction. Circ Res 107:294–304.

  53. 53.

    Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695–702.

  54. 54.

    Thodeti CK, Matthews B, Ravi A, Mammoto A, Ghosh K, Bracha AL, Ingber DE (2009) TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 104:1123–1130.

  55. 55.

    Thoppil RJ, Adapala RK, Cappelli HC, Kondeti V, Dudley AC, Gary Meszaros J, Paruchuri S, Thodeti CK (2015) TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation. Sci Rep 5:14257.

  56. 56.

    Thoppil RJ, Cappelli HC, Adapala RK, Kanugula AK, Paruchuri S, Thodeti CK (2016) TRPV4 channels regulate tumor angiogenesis via modulation of Rho/Rho kinase pathway. Oncotarget 7:25849–25861.

  57. 57.

    Velasquez LS, Sutherland LB, Liu Z, Grinnell F, Kamm KE, Schneider JW, Olson EN, Small EM (2013) Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing. Proc Natl Acad Sci USA 110:16850–16855.

  58. 58.

    Whittaker P, Boughner DR, Kloner RA (1989) Analysis of healing after myocardial infarction using polarized light microscopy. Am J Pathol 134:879–893

  59. 59.

    Wipff PJ, Rifkin DB, Meister JJ, Hinz B (2007) Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 179:1311–1323.

  60. 60.

    Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Mizuno T, Takano H, Hiroi Y, Ueki K, Tobe K et al (1995) Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res 77:258–265.

  61. 61.

    Yong KW, Li Y, Huang G, Lu TJ, Safwani WK, Pingguan-Murphy B, Xu F (2015) Mechanoregulation of cardiac myofibroblast differentiation: implications for cardiac fibrosis and therapy. Am J Physiol Heart Circ Physiol 309:H532–H542.

  62. 62.

    Zhang DX, Mendoza SA, Bubolz AH, Mizuno A, Ge ZD, Li R, Warltier DC, Suzuki M, Gutterman DD (2009) Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo. Hypertension 53:532–538.

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This work was supported by National Institutes of Health (NIH) (R01HL119705, R01HL148585 and R15CA202847; CKT and R01AI144115; SP). We thank Ashot Minsayan for the technical assistance with MI and echocardiography.

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Correspondence to Charles K. Thodeti.

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CKT filed a patent application based on some of the findings in the MS. Rest of the authors declare no conflict of interest.

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Adapala, R.K., Kanugula, A.K., Paruchuri, S. et al. TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation. Basic Res Cardiol 115, 14 (2020).

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  • Cardiac fibroblast
  • Cardiac fibrosis
  • Mechanotransduction
  • Myocardial infarction
  • Rho/Rho kinase
  • TGF-β1
  • TRPV4