Abstract 134: Kidney and Blood Pressure Abnormalities, and Cardiac Enlargement Accompany Moderate Coronary Artery Atherosclerosis in Western Diet Fed SR-BI/LDLR Double Knockout Mice

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 absence, or reduced expression of apoE, respectively. Our lab has generated mice lacking both SR-BI and the LDL receptor (dKO mice). When fed diets that are very high in cholesterol, dKO mice develop rapid CA atherosclerosis and large transmural MIs, and exhibit significantly reduced survival. However, when fed a western type diet (WTD) with only moderately high cholesterol (22% fat, 0.125% cholesterol), dKO mice do not appear to exhibit reduced survival, and develop only mild CA atherosclerosis with little to no cardiac fibrosis. However they have significantly larger hearts than LDLR single KO (sKO) controls fed the same diet for the same period of time. We therefore examined additional factors that may account for the cardiac enlargement observed in these mice such as blood pressure (BP) and kidney pathology. 10 week old dKO mice and sKO controls were fed a WTD for 10 weeks; BP was measured before feeding, and periodically throughout feeding. Mice were euthanized after 10 weeks and blood and tissues were collected for analysis. DKO mice had reduced cholesterol associated with VLDL and LDL sized lipoproteins compared to sKO control mice after 10 weeks of WTD feeding. As expected, heart weights were significantly increased in dKO mice compared to sKO controls. Additionally, dKO mice had significantly lower body weights compared to sKO controls treated equivalently. Before the onset of feeding, there was no significant difference in BP between dKO and sKO mice. After 1 week of WTD feeding, dKO mice had significantly increased BP compared to both pre-diet levels and to sKO controls fed the same diet for the same timeframe. However, BP in dKO mice dropped significantly after 9 weeks of WTD compared to pre-diet measurements, while BP in sKO mice was constant throughout the study. Oil red O staining of kidney sections revealed striking lipid deposition and enlargement of glomeruli in kidneys from dKO mice, this was not observed in sKO control mice.