Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors

Sahoko Ichihara, Koji Obata, Yoshiji Yamada, Kohzo Nagata, Akiko Noda, Gaku Ichihara, Akira Yamada, Tomoko Kato, Hideo Izawa, Toyoaki Murohara, Mitsuhiro Yokota

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor-α (PPAR-α) is a key regulator of lipid and glucose metabolism and is implicated in inflammation. We investigated the effects of the PPAR-α activator fenofibrate on, as well as the role of redox-regulated transcription factors, in the development of left ventricular (LV) hypertrophy and heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed a high-salt diet and treated with either fenofibrate (30 or 50 mg/kg per day) or vehicle from 7 weeks of age. Fenofibrate inhibited the development of compensated hypertensive LV hypertrophy, attenuated the LV relaxation abnormality and systolic dysfunction, and improved the survival rate in DS rats. It also prevented a decrease in the ratio of reduced to oxidized glutathione and inhibited up-regulation of the DNA binding activities of the redox-regulated transcription factors NF-κB, AP-1, Egr-1, SP1, and Ets-1 induced in the left ventricle by the high-salt diet. Expression of target genes for these transcription factors, including those for adhesion molecules (VCAM-1, ICAM-1), cytokines (MCP-1), growth factors (TGF-β, PDGF-B), and osteopontin, was also increased by the high-salt diet in a manner sensitive to treatment with fenofibrate. Furthermore, the infiltration of macrophages and T lymphocytes into the left ventricle and the increase in the plasma concentration of C-reactive protein were inhibited by fenofibrate. The PPAR-α activator fenofibrate thus attenuated the progression of heart failure and improved the survival rate in this rat model. These effects were associated with inhibition of the inflammatory response and of activation of redox-regulated transcription factors in the left ventricle.

Original languageEnglish
Pages (from-to)318-329
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume41
Issue number2
DOIs
Publication statusPublished - 01-08-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Attenuation of cardiac dysfunction by a PPAR-α agonist is associated with down-regulation of redox-regulated transcription factors'. Together they form a unique fingerprint.

  • Cite this