Abstract 2893: Enhanced Myocardial Ischemic Tolerance in Hypercholesterolemic APOE Knockout Mice is Associated with Increased Expression of Caveolin 1 and Metallothionein
Hypercholesterolemia (HC) is an established risk factor for atherosclerosis and vascular endothelial dysfunction. Paradoxically, we and other investigators have found that animals with HCL are more resistant to myocardial ischemia-reperfusion (Isch-Rep) injury. However, the molecular mechanisms underlying this clinically relevant ischemia-resistant phenotype remain poorly understood. To this context, the present study was designed to identify novel molecular mediators for the HC-induced cardioprotection against Isch-Rep injury. Adult male C57BL/6J wild-type (C57BL-WT) mice and homozygous apolipoprotein E knockout (APOE-KO) mice were fed with regular rodent chow. The hearts were isolated and subjected to 20 min of zero-flow global Isch and 30 min of Rep in Langendorff mode. Infarct size and ventricular contractile function were assessed. Blood samples were collected from each mouse after the heart isolation procedure to measure serum total cholesterol (TCL). As summarized in Table 1⇓, the APOE-KO mice had developed HC, which was accompanied with significantly better post-Isch cardiac contractile function (DF and ±df/dtmax) and smaller infarct size as compared with C57BL-WT control mice. In a parallel series of experiments, heart tissues were collected from C57BL-WT and APOE-KO mice and total tissue lysates were prepared for Western blot analysis. We found significant enhancement in cardiac expression of caveolin 1 (Cav-1) and metallothionein (MT) in APOE-KO mice, whereas caveolin 3 (Cav-3) and T-complex protein 1beta (TCP-1beta) were significantly downregulated under HC. Electron microscopy revealed a selective increase in caveolae density on the endothelial cell membranes of APOE-KO mice. This study has provided the first evidence demonstrating that the remarkable ischemia-resistant phenotype of HC is associated with enhanced expression of two cytoprotective proteins - Cav-1 and MT in the heart.
This research has received full or partial funding support from the American Heart Association, AHA National Center.