Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide

Abstract

It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive potassium channels (KATP). Hearts isolated from rats fed 2% cholesterol-enriched diet or normal diet for 8 weeks were subjected to 30 min global ischemia and 120 min reperfusion in the presence or absence of KATP modulators. After normal diet, either the non-selective KATP activator cromakalim at 10-5 M or the selective mitochondrial KATP (mitoKATP) opener diazoxide at 3x10-5 M significantly decreased infarct size when compared to vehicle-treated controls. Their cardioprotective effect was abolished by co-administration of the non-selective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet may influence cardiac KATP channels. Cardiac expression of KATP subunit gene (Kir6.1) was significantly down-regulated in cholesterol-fed rats, however, protein levels of Kir6.1 and 6.2 were not changed. Cholesterol diet significantly decreased cardiac ATP and increased lactate content and enhanced myocardial oxidative stress as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.