title: Attenuation of cardiac dysfunction by a PPAR-alpha agonist is associated with down-regulation of redox-regulated transcription factors.
abstract: Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a key regulator of lipid and glucose metabolism and is implicated in inflammation. We investigated the effects of the PPAR-alpha 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-kappaB, 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-beta, 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-alpha 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.
authors.affiliation: Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Japan. saho@gene.mie-u.ac.jp
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Koji
authors.initials: K
authors.lastname: Obata
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Akiko
authors.initials: A
authors.lastname: Noda
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
authors.forename: Akira
authors.initials: A
authors.lastname: Yamada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kato
authors.forename: Hideo
authors.initials: H
authors.lastname: Izawa
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D011345:Fenofibrate / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D014157:Transcription Factors / Q000096:biosynthesis*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D005947:Glucose; D011345:Fenofibrate