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Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway.
Circulation. 2004 Feb 24; 109(7):904-10.Circ

Abstract

BACKGROUND

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, nuclear factor-kappaB, and AP-1. However, the roles of PPAR-alpha activators in endothelin (ET)-1-induced cardiac hypertrophy are not yet known.

METHODS AND RESULTS

First, in cultured neonatal rat cardiomyocytes, a PPAR-alpha activator, fenofibrate (10 micromol/L), and PPAR-alpha overexpression 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 PPAR-alpha activator 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 beta-myosin heavy chain mRNA) in AB rats.

CONCLUSIONS

These results suggest that PPAR-alpha activation 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.

Authors+Show Affiliations

Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14967736

Citation

Irukayama-Tomobe, Yoko, et al. "Endothelin-1-induced Cardiac Hypertrophy Is Inhibited By Activation of Peroxisome Proliferator-activated Receptor-alpha Partly Via Blockade of c-Jun NH2-terminal Kinase Pathway." Circulation, vol. 109, no. 7, 2004, pp. 904-10.
Irukayama-Tomobe Y, Miyauchi T, Sakai S, et al. Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway. Circulation. 2004;109(7):904-10.
Irukayama-Tomobe, Y., Miyauchi, T., Sakai, S., Kasuya, Y., Ogata, T., Takanashi, M., Iemitsu, M., Sudo, T., Goto, K., & Yamaguchi, I. (2004). Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway. Circulation, 109(7), 904-10.
Irukayama-Tomobe Y, et al. Endothelin-1-induced Cardiac Hypertrophy Is Inhibited By Activation of Peroxisome Proliferator-activated Receptor-alpha Partly Via Blockade of c-Jun NH2-terminal Kinase Pathway. Circulation. 2004 Feb 24;109(7):904-10. PubMed PMID: 14967736.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway. AU - Irukayama-Tomobe,Yoko, AU - Miyauchi,Takashi, AU - Sakai,Satoshi, AU - Kasuya,Yoshitoshi, AU - Ogata,Takehiro, AU - Takanashi,Masakatsu, AU - Iemitsu,Motoyuki, AU - Sudo,Tatsuhiko, AU - Goto,Katsutoshi, AU - Yamaguchi,Iwao, Y1 - 2004/02/16/ PY - 2004/2/18/pubmed PY - 2004/6/2/medline PY - 2004/2/18/entrez SP - 904 EP - 10 JF - Circulation JO - Circulation VL - 109 IS - 7 N2 - BACKGROUND: 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, nuclear factor-kappaB, and AP-1. However, the roles of PPAR-alpha activators in endothelin (ET)-1-induced cardiac hypertrophy are not yet known. METHODS AND RESULTS: First, in cultured neonatal rat cardiomyocytes, a PPAR-alpha activator, fenofibrate (10 micromol/L), and PPAR-alpha overexpression 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 PPAR-alpha activator 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 beta-myosin heavy chain mRNA) in AB rats. CONCLUSIONS: These results suggest that PPAR-alpha activation 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/14967736/Endothelin_1_induced_cardiac_hypertrophy_is_inhibited_by_activation_of_peroxisome_proliferator_activated_receptor_alpha_partly_via_blockade_of_c_Jun_NH2_terminal_kinase_pathway_ L2 - https://www.ahajournals.org/doi/10.1161/01.CIR.0000112596.06954.00?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -