Abstract 337: Extensive Coronary Artery Atherosclerosis and Myocardial Infarction in SR-BI/LDLR Double Knockout Mice Fed 4 Different Atherogenic Diets

abstract

Mice lacking the HDL receptor, SR-BI, are susceptible to spontaneous or diet-inducible occlusive coronary artery (CA) atherosclerosis and myocardial infarction (MI) in the context of an absence, or mutated form of apoE, respectively. We tested the effects of SR-BI deficiency on aortic sinus and CA atherosclerosis in LDL receptor deficient mice fed four different atherogenic diets; the HFCC and HFC diets are composed of 15% fat, 1.25% cholesterol and either contain or lack 0.5% sodium cholate, respectively, the HC diet is a normal chow diet supplemented with 2% cholesterol, and the western diet contains 21% butter fat and 0.15% cholesterol. SR-BI/LDLR double knockout (dKO) mice fed the HFCC and HFC diets exhibited reduced survival; average survival was 3.5 and 9.5 weeks, respectively. Reduced survival was not observed in LDLR single knockout (sKO) control mice. Plasma lipoprotein cholesterol levels and triglyercide secretion rates were lower in dKO mice compared to sKO mice. Conversely, dKO mice developed significantly larger atherosclerotic plaques in their aortic sinuses compared to sKO mice, and severe occlusive CA atherosclerosis which was not observed in sKO mice. DKO mice fed the HC diet or western diet did not exhibit reduced survival up to 12 weeks of feeding, however CA atherosclerosis was still observed. CA atherosclerosis was accompanied by platelet positive staining and myocardial fibrosis, indicating MI. CA plaques in dKO mice were characterized by the presence of collagen and both CD68 and smooth muscle actin positive staining, indicating complex fibrous plaques consisting of both macrophages and smooth muscle cells. Plaque free CAs and CAs containing small, non-occlusive plaques stained positive for markers of activated endothelium. Importantly, dKO mice fed the HC diet had largest burden of atherosclerosis in their aortic sinuses whereas the extent of atherosclerosis in their CAs was the mild in comparison to that observed dKO mice fed the HFCC and HFC diets. This observation suggests that the development of atherosclerosis in the CAs and the aortic sinus are influenced by different factors.