Arterial retention of remnant lipoproteins ex vivo is increased in insulin resistance because of increased arterial biglycan and production of cholesterol-rich atherogenic particles that can be improved by ezetimibe in the JCR:LA-cp rat.

Literature supports the response-to-retention hypothesis-that during insulin resistance,impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. we used the jcr:la-cp rat model of metabolic syndrome (mets) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance. arteries from control and mets (insulin-resistant) jcr:la-cp rats were perfused ex vivo with cy5-labeled remnant lipoproteins,and their arterial retention was quantified by confocal microscopy. arterial proteoglycans were isolated from control and mets rats at 6,12,and 32 weeks of age. there was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in mets rats as compared to control rats. mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants,as compared to controls. additionally,perfusion of vessels treated with ezetimibe,alone or in combination with simvastatin,with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls. increased progression of atherosclerotic cardiovascular disease in mets and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. furthermore,ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and mets.