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.