Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 1, Issue 5, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.112.003434
Keywords
arterial remodeling; biglycan; metabolic syndrome; triglyceride-rich remnant lipoproteins
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Funding
- Heart and Stroke (HSFA) grant-in-aid
- Medical School Grant from Merck Pharmaceuticals
- Muttart/Collip studentship
- University of Alberta
- Heart and Stroke Foundation of Canada
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Background-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. Methods and Results-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. Conclusions-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.
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