Hypolipidemic compound
pirinixic acid (WY-14643, WY) is known to exert pleiotropic (other than primary) effects, such as activation of
peroxisome proliferator-activated receptors (
PPAR-alpha),
transcription factors regulating different cardiac functions. Their role in
ischemia-reperfusion (I/R) injury and cardioprotection is less clear, although protective effects of
PPAR agonists have been documented. This study was designed to explore the effects of WY on the I/R injury in the rat heart and potential mechanisms involved, including mitochondrial K(
ATP) channels (
mitoK(ATP)) opening and production of
reactive oxygen species (ROS). Langendorff-perfused hearts of rats intragastrally treated with WY (3 mg/kg/day) for 5 days and of control animals were subjected to 30-min global
ischemia and 2-h reperfusion with or without 15-min perfusion with
mitoK(ATP) blocker
5-hydroxydecanoate (5-HD) prior to I/R. Evaluation of the
infarct size (IS, TTC staining) served as the main end-point of protection. Lipid peroxidation (a marker of ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD), whereas
protein expression of endothelial
NO synthase was analysed by Western blotting. A 2-fold increase in the cardiac
protein levels of eNOS
after treatment with WY was accompanied by lower post-I/R levels of CD compared with those in the hearts of untreated controls, although WY itself enhanced ROS generation prior to
ischemia. IS was reduced by 47 % in the hearts of WY-treated rats (P<0.05), and this effect was reversed by 5-HD. Results suggest that
PPAR-alpha activation may confer protection against lethal I/R injury in the rat heart that involves up-regulation of eNOS,
mitoK(ATP) opening and reduced oxidative stress during I/R.