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ROLE OF MECHANOSENSITIVE ION CHANNEL TRPV4 IN CARDIAC REMODELING

Adapala, Ravi kumar
http://orcid.org/0000-0002-4082-5301
http://rave.ohiolink.edu/etdc/view?acc_num=kent1520341694907018

Abstract Details

2018, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
ABSTRACT Ischemic heart disease (IHD) is the major underlying cause of myocardial infarction (MI), scarring, and hypertrophy leading to heart failure which is one of the leading causes of death. Cardiac remodeling following induced pressure overload/myocardial infarction is a multiphase reparative process which involves replacement of damaged tissue with physiological (reparative) fibrosis to form scar that limit the expansion of the left ventricle/infarct of the heart. Although therapeutic approaches targeting soluble factor (ex: ACE inhibitors, ARBs, TGF-ß inhibitors: Pirfenidone, Halofuginone) signaling is available for the treatment of cardiac fibrosis and hypertrophy, they showed modest efficacy in clinics. Hence, it is indispensable to identify and develop an alternate and novel therapeutics to treat the heart failure. Mechanical cues are indeed necessary to integrate with soluble factor associated signaling to maintain cardiac physiological functions. Of late, TRPV4 has been shown to be mechanosensor and our lab has established that TRPV4 is a key mechanosensor in endothelial cells and cardiac fibroblasts (CF) and plays an important role in cardiovascular pathophysiology. We have recently demonstrated that TRPV4 mediates cardiac fibroblast differentiation into myofibroblasts in vitro. However, the physiological significance of TRPV4 in cardiac remodeling in vivo is not known. Based on our previous findings, we hypothesized that targeting TRPV4 may offer cardioprotection following pressure overload-induced hypertrophy and myocardial infarction. The first aim of the dissertation was to determine whether TRPV4 mediated mechanotransduction preserves the heart integrity and reduce fibrosis in vivo following pressure overload-induced hypertrophy. By inducing pressure overload hypertrophy (TAC), we found that TRPV4 knockout (KO) mice exhibited improved cardia function, decreased myocardial cross sectional area and left ventricular mass when compared with WT. Further, we have also revealed that TRPV4 KO mice hearts showed less cardiac fibrosis compared to WT. To unravel the unexplored integration of soluble and mechanical signaling behind the cardiac fibrosis, the second aim of this dissertation was to delineate the molecular mechanisms by which TRPV4 regulate cardiac fibroblasts differentiation into myofibroblasts. Our in vitro studies revealed that TGF-ß1 mediated fibroblasts differentiation was attenuated in TRPV4KO mCF compared WT mCF. Further, both TGF-ß1 and a specific activator of TRPV4, GSK1016790A, significantly enhanced pro-fibrotic a-SMA and Col1a1 promoter activities. Importantly, we have dissected the mechanism and found that both TGF-ß1 and GSK (TRPV4 agonist) induced TRPV4-dependent activation of the Rho/Rho Kinase pathway as well as a mechanosensitive transcription factor MRTF-A are involved in CF differentiation. To further corroborate the critical role of TRPV4 in cardiac remodeling, the third aim of this dissertation was to ascertain the functional role of TRPV4 in cardio protection following myocardial infarction. We found that after 8 weeks post- MI, significant improvement of cardiac function was observed in TRPV4KO mice compared to WT. Further, we found reduced cardiac fibrosis at infarct and remote zones in TRPV4KO-MI mice compared to WT-MI mice which display enhanced fibrosis at infarct/border zone as well as remote zones. Furthermore, TRPV4KO hearts exhibited decreased cardiomyocyte apoptosis (TUNEL assay) and increased capillary density (CD31 staining) post-MI compared to WT hearts. In conclusion, our results suggest that targeting a mechanosensor TRPV4, protects heart from induced pressure overload or myocardial infarction-induced damage by preserving cardiac structure, function and identifies TRPV4 as a novel therapeutic target for heart failure.
CHARLES THODETI, PH.D. (Advisor)
WILLIAM CHILIAN, PH.D (Committee Member)
LIYA YIN, PH.D (Committee Member)
MOSES OYEWUMI, PH.D (Committee Member)
GARY KOSKI, PH.D (Committee Member)
134 p.
Biology; Biomedical Research
TRPV4, Cardiac Fibrosis, Mechanotransduction, Myocardial infarction, Cardiac fibroblasts, cardiac remodeling

Recommended Citations

Citations

  • Adapala, R. K. (2018). ROLE OF MECHANOSENSITIVE ION CHANNEL TRPV4 IN CARDIAC REMODELING [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1520341694907018

    APA Style (7th edition)

  • Adapala, Ravi kumar. ROLE OF MECHANOSENSITIVE ION CHANNEL TRPV4 IN CARDIAC REMODELING. 2018. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1520341694907018.

    MLA Style (8th edition)

  • Adapala, Ravi kumar. "ROLE OF MECHANOSENSITIVE ION CHANNEL TRPV4 IN CARDIAC REMODELING." Doctoral dissertation, Kent State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1520341694907018

    Chicago Manual of Style (17th edition)

kent1520341694907018
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This open access ETD is published by Kent State University and OhioLINK.