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 (PϽ0.05) smaller in the LDLr -/-mice compared with wild-type mice (24.7Ϯ3.2% and 38.8Ϯ4.3% 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 (PϽ0.01) in myocardial necrosis per AAR (50.2Ϯ5.36% 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 (PϽ0.05) decrease in necrosis per AAR, which was 22.5Ϯ3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8Ϯ4.3% of AAR). LDLr -/-mice on the same long-term HCD showed a similar significantly (PϽ0.05) decreased infarct size, which was 13.2Ϯ4.0% 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. (Arterioscler Thromb Vasc Biol. 1999;19:2776-2781.)Key Words: infarct Ⅲ cholesterol Ⅲ neutrophils Ⅲ mutant mice T here is a large body of evidence indicating that the best-known risk factor for the development of coronary artery disease is elevated plasma lipid levels. 1-3 Furthermore, a number of prospective studies have established that the risk of cardiac morbidity and mortality is directly related to the concentration of plasma cholesterol. 2,3 Despite the development of a number of agents that effectively reduce serum cholesterol levels in patients, coronary arteriosclerosis and subsequent myocardial infarction (MI) still represent a major health concern in our society. The majority of previous studies concerning the pathobiology of myocardial ischemiareperfusion (MI-R) injury have been derived from animals that are otherwise normal. Although the data derived from these studies provide meaningful insights into the mechanisms of cellular injury after MI-R, the relevance of these findings to those human populations that are at greatest risk for developing myocardial reperfusion injury remains unclear.Previous studies investigating the effects of MI-R in the setting of hypercholesterolemia have focused primarily on rabbit models of ischemia alone 4,5...

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