TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation.
Mechanotransduction; TRPV4; Myocardial infarction; Myocardial infarction; TGF-beta1; Rho/Rho kinase; Mechanotransduction; TGF-β1; Myocardial infarction; EXTRACELLULAR matrix; HEART failure; HEART fibrosis; HEART; Cardiac fibroblast; Cardiac fibrosis; Rho/Rho kinase; TRPV4; Cardiac fibroblast; Cardiac fibrosis; DELETION mutation
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-beta 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
Adapala Ravi K; Kanugula Anantha K; Paruchuri Sailaja; Chilian William M; Thodeti Charles K
Basic research in cardiology
2020
2020-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1007/s00395-020-0775-5" target="_blank" rel="noreferrer noopener">10.1007/s00395-020-0775-5</a>
A Novel TRPV4-dependent Mechanotranscription Pathway Regulates Cardiac Fibrosis Following Pressure-Overload
cardiac fibroblast; Cardiovascular System & Cardiology; fibrosis; Hematology; mechanical signaling; myofibroblast; TRPV4
Adapala R K; Cappelli H; Ohanyan V A; Thoppil R; Luli J; Paruchuri S; Chilian W M; Meszaros J G; Thodeti C
Circulation Research
2015
2015-12
Journal Article or Conference Abstract Publication
n/a
Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase
adrenomedullin; angiotensin-ii; cardiac fibroblast; cyclic AMP; extracellular-matrix; failure; fibrosis; gene-expression; growth-factor-beta; heart; lung fibroblasts; modulation; necrosis-factor-alpha; phenotypic; rat ventricular myocytes; Science & Technology - Other Topics; smooth muscle actin
Transformation of fibroblasts to myofibroblasts, characterized by expression of alpha-smooth muscle actin (alpha-SMA) and production of extracellular matrix (ECM) components, is a key event in connective tissue remodeling. Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by cardiac fibroblasts (CFs) causes fibrosis, myocardial stiffening, and cardiac dysfunction. We tested whether adenylyl cyclase (AC) activation (increased cAMP levels) modulates the transformation of adult rat CF to myofibroblasts, as assessed by immunofluorescent microscopy, immunoblotting, and collagen synthesis. A 24-h incubation of CF with TGF-beta or angiotensin II increased alpha-SMA expression, which was inhibited by the AC agonist forskolin and a cAMP analog that activates protein kinase A. Treatment with forskolin blunted serum-, TGF-beta-, and angiotensin II-stimulated collagen synthesis. CFs engineered to overexpress type 6 AC had enhanced forskolin-promoted cAMP formation, greater inhibition by forskolin of TGF-beta-stimulated alpha-SMA expression, and a decrease in the EC50 of forskolin to reduce serum-stimulated collagen synthesis. The AC stimulatory agonist adrenomedullin inhibited collagen synthesis in CF that overexpressed AC6 but not in controls. Thus, AC stimulation blunts collagen synthesis and, in parallel, the transformation of adult rat CF to myofibroblasts. AC overexpression enhances these effects, "uncovering" an inhibition by adrenomedullin. These findings implicate cAMP as an inhibitor of ECM formation by means of blockade of the transformation of CF to myofibroblasts and suggest that increasing AC expression, thereby enhancing cAMP generation through stimulation of receptors expressed on CF, could provide a means to attenuate and prevent cardiac fibrosis and its sequelae.
Swaney J S; Roth D M; Olson E R; Naugle J E; Meszaros J G; Insel P A
Proceedings of the National Academy of Sciences of the United States of America
2005
2005-01
Journal Article
<a href="http://doi.org/10.1073/pnas.0408704102" target="_blank" rel="noreferrer noopener">10.1073/pnas.0408704102</a>
A TRP to cardiac fibroblast differentiation.
Female; Humans; Male; Animals; TRPV4; *Wound Healing; TRPV Cation Channels/*metabolism; integrin; *Cell Differentiation; cardiac fibroblast; myofibroblast; *Calcium Signaling; *Cell Transdifferentiation; Atrial Fibrillation/*metabolism; differentiation; ECM stiffness; Fibroblasts/*metabolism/*physiology; mechanical signaling; Myofibroblasts/*cytology/*metabolism; Rho/ROCK; TRPC Cation Channels/*metabolism; TRPM Cation Channels/*metabolism; Cellular; *Mechanotransduction
The differentiation of cardiac fibroblasts to myofibroblasts is one of the key events during cardiac remodeling, however, the molecular mechanism underlying this process is not well known. Calcium signaling plays an important role in the regulation of cardiac fibroblast function, but its role in the differentiation of fibroblasts is undefined. Recently four Transient Receptor Potential (TRP) channels TRPM7, TRPC3, TRPC6 and TRPV4 were shown to be crucial for the differentiation of cardiac fibroblasts to myofibroblasts. This addendum sums up the roles described for these four TRP channels in cardiac fibroblast differentiation, and discusses the possible molecular mechanisms underlying this process and its relevance for cardiac remodeling in disease.
Thodeti Charles K; Paruchuri Sailaja; Meszaros J Gary
Channels (Austin, Tex.)
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.4161/chan.24328" target="_blank" rel="noreferrer noopener">10.4161/chan.24328</a>
Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts.
*Cell Differentiation; Animals; Blood Glucose/metabolism; cardiac fibroblast; Cell Movement; Cell Proliferation; Cells; collagen; Collagen/metabolism; collagene; concentration elevee de glucose; Cultured; diabete; diabetes; fibroblaste cardiaque; Fibroblasts/*metabolism/pathology; Fibrosis; high glucose; Hyperglycemia/*metabolism/pathology; Male; migration; Myocardium/*metabolism/pathology; myofibroblast; myofibroblastes; proliferation; Rats; Signal Transduction; Sprague-Dawley
Diabetes is an independent risk factor for cardiovascular disease that can eventually cause cardiomyopathy and heart failure. Cardiac fibroblasts (CF) are the critical mediators of physiological and pathological cardiac remodeling; however, the effects of hyperglycemia on cardiac fibroblast function and differentiation is not well known. Here, we performed a comprehensive investigation on the effects of hyperglycemia on cardiac fibroblasts and show that hyperglycemia enhances cardiac fibroblast function and differentiation. We found that high glucose treatment increased collagen I, III, and VI gene expression in rat adult cardiac fibroblasts. Interestingly, hyperglycemia increased CF migration and proliferation that is augmented by collagen I and III. Surprisingly, we found that short term hyperglycemia transiently inhibited ERK1/2 activation but increased AKT phosphorylation. Finally, high glucose treatment increased spontaneous differentiation of cardiac fibroblasts to myofibroblasts with increasing passage compared with low glucose. Taken together, these findings suggest that hyperglycemia induces cardiac fibrosis by modulating collagen expression, migration, proliferation, and differentiation of cardiac fibroblasts.
Shamhart Patricia E; Luther Daniel J; Adapala Ravi K; Bryant Jennifer E; Petersen Kyle A; Meszaros J Gary; Thodeti Charles K
Canadian journal of physiology and pharmacology
2014
2014-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1139/cjpp-2013-0490" target="_blank" rel="noreferrer noopener">10.1139/cjpp-2013-0490</a>