Effects of hypercholesterolemia on myocardial ischemia-reperfusion injury in LDL receptor-deficient mice

Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipopr otein receptor-deficient (LDLr -/-) and control (wild-type) mice to 30 minu tes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infar ction per area at risk (AAR) was noted under baseline conditions to be sign ificantly (P<0.05) smaller in the LDLr -/- mice compared with wild-type mic e (24.7+/-3.2% and 38.8+/-4.3% of AAR, respectively). Subsequently, mice we re fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in s ignificant increases in serum cholesterol levels in both LDLr -/- and wild- type groups. After 2 weeks of the HCD, the LDLr -/- mice demonstrated a sig nificant 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 significa nt (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 A AR). 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 addi tional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly i ncreased 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 h eart.