Fibronectin Gene Expression in Aortic Regurgitation: Relative Roles of Mitogen-Activated Protein KinasesTruter S.L. · Catanzaro D.F. · Supino P.G. · Gupta A. · Carter J. · Ene A.R. · Herrold E.M. · Dumlao T.F. · Beltran F. · Borer J.S.
aWyeth Research, Collegeville, Pa., bThe Division of Cardiovascular Medicine and The Howard Gilman Institute for Heart Valve Disease, State University of New York Downstate Medical Center, Brooklyn, N.Y., cColumbia University Medical Center, New York, N.Y., and dBoston Medical Center, South Boston, Mass., USA
Objectives: In aortic regurgitation (AR), fibronectin (FN) expression is upregulated. This study sought to determine signal transduction pathways involved in upregulation of FN expression in AR. Methods: Cardiac fibroblasts (CF) from rabbits with surgically induced AR and matched controls (NL) were cultured and assayed for FN expression and kinase activity with and without inhibitors of kinases JNK, p38 mitogen-activated protein kinase (MAPK) and extracellular response kinase (ERK). NL CF also were subjected to cyclic strain mimicking AR for 24 h in culture with and without inhibitors. Results: AR CF exhibited 2.9-fold greater c-Jun phosphorylation (p < 0.01) and 1.5- to 2-fold greater ATF2 phosphorylation (p < 0.05–0.01) than NL. JNK and p38MAPK inhibition reduced c-Jun and ATF2 phosphorylation to NL; ERK inhibition had no effect. FN mRNA expression was similar in pattern to kinase activities. Cyclic strain in NL CF increased c-Jun phosphorylation 2-fold versus unstrained controls (p < 0.005). This was suppressed by inhibition of JNK but not p38MAPK. Conclusion: FN expression in response to the acute mechanical strain resembling AR is upregulated primarily via JNK. However, in chronic AR both JNK and p38MAPK are involved. These signaling pathways represent potential therapeutic targets for normalizing extracellular matrix (ECM) composition and contractile force transmission, believed to be related to ECM composition/organization, in AR.