Activation of Peroxisome Proliferator-activated Receptor-α Decreases Endothelin-1-induced p38 Mitogen-activated Protein Kinase Activation in Cardiomyocytes

Endothelin-1 (ET-1) is synthesized and secreted by cardiomyocytes and induces cardiac hypertrophy. Peroxisome proliferator-activated receptor-α (PPAR-α) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, such as nuclear factor-κB and activator protein-1 (AP-1). We reported that PPAR-α activator, fenofibrate (10 μM), and PPAR-α overexpression markedly inhibited the ET-1-induced increase in protein synthesis in cultured neonatal rat cardiomyocytes. Activation of protein kinase C and one or more of the mitogen-activated protein kinase cascades by ET-1 induces many of the features of hypertrophy.We demonstrated that PPAR-α activation significantly inhibits ET-1-induced cardiac hypertrophy through negative regulation of AP-1 binding activity partly secondary to inhibition of the JNK pathway. Zechner et al. demonstrated a significant role of p38 mitogen-activated protein kinase (p38) in myocardial cell hypertrophic growth and gene expression. Therefore, we investigated the effect of fenofibrate on ET-1-induced p38 activation in cardiomyocytes. The phosphorylation of p38 was transiently increased after 15 and 30 minutes of stimulation with ET-1, which was significantly inhibited by fenofibrate (10 μM). Neither application of ET-1 nor fenofibrate treatment affected the expression level of p38 in cardiomyocytes. These results suggest that the negative effect of the PPAR-α activator, fenofibrate, on ET-1-induced cardiac hypertrophy may be partly due to inhibition of the p38 signaling pathway.