Abstract 647: Hyperglycemia Increases Diet-Induced Coronary Artery Disease and Myocardial Infarction in SRBI Knockout ApoE-Hypomorphic Mice

Background: Type I diabetes is characterized by high levels of glucose and free fatty acids in plasma. Several epidemiological studies have established diabetes as an independent risk factor for the development of cardiovascular disease. Diabetic animal models have shown increased development of aortic atherosclerosis, however the impact on coronary artery (CA) disease is less clear. Conventional mouse models of atherosclerosis do not reproducibly develop CA atherosclerosis. The HDL receptor, SRBI, has been associated with protection against atherosclerosis. SRBI knockout (KO) ApoE-hypomorphic mice exhibit increased aortic sinus atherosclerosis and diet-induced occlusive CA atherosclerosis when compared to SRBI+/+ ApoE-hypomorphic mice. We assessed the hypothesis that diabetes will increase the development of CA and aortic atherosclerosis and myocardial infarction in SRBI KO ApoE-hypomorphic mice. Methods: Hyperglycemia was induced by multiple low-dose i.p. injections of streptozotocin (40 mg/kg body weight). Controls received vehicle. Mice were fed a regular chow diet for 11 weeks (n=6-7) or a high-fat/high-cholesterol diet for 4 weeks (n=14-15). CA and aortic atherosclerosis and cardiac fibrosis were evaluated. Results: Diabetic SRBI KO ApoE-hypomorphic mice maintained on normal chow diet exhibited small plaques in the aortic sinus and the burden of atherosclerosis in CA was low. No fibrosis in hearts was detected. When mice were challenged with a high-fat/high-cholesterol diet, survival was significantly reduced in the diabetic group (p<0.01 vs control). High-fat/high-cholesterol diet fed diabetic mice exhibited significantly larger plaques in the aortic sinus as well (p<0.05 vs control). CA atherosclerosis burden was increased (p<0.001 vs control) along with higher levels of cardiac fibrosis (p<0.01 vs control). Conclusion: Hyperglycemia significantly increased the burden of aortic and CA atherosclerosis and cardiac fibrosis in SRBI KO ApoE-hypomorphic mice fed a high-fat/high-cholesterol diet.