Activation of peroxisome proliferator-activated receptor-alpha 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-alpha (PPAR-alpha) is a lipid-activated nuclear receptor that negatively regulates the vascular inflammatory gene response by interacting with transcription factors, such as nuclear factor-kappaB and activator protein-1 (AP-1). We reported that PPAR-alpha activator, fenofibrate (10 microM), and PPAR-alpha 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-alpha 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 microM). 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-alpha activator, fenofibrate, on ET-1-induced cardiac hypertrophy may be partly due to inhibition of the p38 signaling pathway.
Irukayama-Tomobe
Yoko
Y
Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Miyauchi
Takashi
T
Kasuya
Yoshitoshi
Y
Sakai
Satoshi
S
Goto
Katsutoshi
K
Yamaguchi
Iwao
I
D000818:Animals; D000831:Animals, Newborn; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology*; D006984:Hypertrophy; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019332:Endothelin-1; D047493:PPAR alpha; D048051:p38 Mitogen-Activated Protein Kinases; D011345:Fenofibrate