Endothelin-1–Induced Cardiac Hypertrophy Is Inhibited by Activation of Peroxisome Proliferator–Activated Receptor- Partly Via Blockade of c-Jun NH2-Terminal Kinase Pathway

Background—Peroxisome proliferator-activated receptor(PPAR) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, nuclear factorB, and AP-1. However, the roles of PPARactivators in endothelin (ET)-1–induced cardiac hypertrophy are not yet known. Methods and Results—First, in cultured neonatal rat cardiomyocytes, a PPARactivator, fenofibrate (10 mol/L), and PPARoverexpression markedly inhibited the ET-1–induced increase in protein synthesis. Second, fenofibrate markedly inhibited ET-1–induced increase in c-Jun gene expression and phosphorylation of c-Jun and JNK. These results suggest that this PPARactivator interferes with the formation and activation of AP-1 protein induced by ET-1 in cardiomyocytes. Third, fenofibrate significantly inhibited the increase of ET-1 mRNA level by ET-1, which was also confirmed by luciferase assay. Electrophoretic mobility shift assay revealed that fenofibrate significantly decreased the ET-1–stimulated or phorbol 12-myristate 13-acetate–stimulated AP-1 DNA binding activity, and the nuclear extract probe complex was supershifted by anti-c-Jun antibody. Fourth, 24 hours after aortic banding (AB) operation, fenofibrate treatment significantly inhibited left ventricular hypertrophy and hypertrophy-related gene expression pattern (ET-1, brain natriuretic peptide, and -myosin heavy chain mRNA) in AB rats. Conclusions—These results suggest that PPARactivation interferes with the signaling pathway of ET-1–induced cardiac hypertrophy through negative regulation of AP-1 binding activity, partly via inhibition of the JNK pathway in cultured cardiomyocytes. We also revealed that fenofibrate treatment inhibited left ventricle hypertrophy and phenotypic changes in cardiac gene expression in AB rats in vivo. (Circulation. 2004;109:904-910.)