Effects of Hypercholesterolemia on Myocardial Ischemia-Reperfusion Injury in LDL Receptor–Deficient Mice

Abstract

Abstract —Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipoprotein receptor–deficient (LDLr –/–) and control (wild-type) mice to 30 minutes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infarction per area at risk (AAR) was noted under baseline conditions to be significantly ( P <0.05) smaller in the LDLr –/– mice compared with wild-type mice (24.7±3.2% and 38.8±4.3% of AAR, respectively). Subsequently, mice were fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in significant increases in serum cholesterol levels in both LDLr –/– and wild-type groups. After 2 weeks of the HCD, the LDLr –/– mice demonstrated a significant elevation ( P <0.01) in myocardial necrosis per AAR (50.2±5.36% of AAR) compared with the normal-diet LDLr –/– group, whereas the short-term HCD-fed wild-type mice demonstrated no significant difference from baseline. In contrast, wild-type mice fed the HCD for 12 weeks revealed a significant ( P <0.05) decrease in necrosis per AAR, which was 22.5±3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8±4.3% of AAR). LDLr –/– mice on the same long-term HCD showed a similar significantly ( P <0.05) decreased infarct size, which was 13.2±4.0% of the AAR. In additional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly increased after 12 weeks of the HCD in the LDLr –/– mouse heart. These data suggest that short-term cholesterol feeding renders the myocardium of LDLr –/– mice more susceptible to ischemia-reperfusion injury, whereas more long-term hypercholesterolemia confers cardioprotection in the LDLr –/– mouse heart.