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Activation of peroxisome proliferator-activated receptor-alpha decreases endothelin-1-induced p38 mitogen-activated protein kinase activation in cardiomyocytes.

Abstract：

: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.

journal_name

J Cardiovasc Pharmacol

journal_title

Journal of cardiovascular pharmacology

authors

Irukayama-Tomobe Y,Miyauchi T,Kasuya Y,Sakai S,Goto K,Yamaguchi I

doi

10.1097/01.fjc.0000166303.33313.01

subject

Has Abstract

pub_date

2004-11-01 00:00:00

pages

S358-61

eissn

0160-2446

issn

1533-4023

pii

00005344-200411001-00087

journal_volume

44 Suppl 1

pub_type

杂志文章

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Activation of peroxisome proliferator-activated receptor-alpha decreases endothelin-1-induced p38 mitogen-activated protein kinase activation in cardiomyocytes.