The mechanisms underlying the initiation and development of atherosclerosis are not fully understood. As outlined in the response to retention hypothesis, the retention of atherogenic lipoproteins within the sub-endothelial space by their interactions with vascular proteoglycans is thought to be one of the earliest steps in the development of atherosclerosis. LDL that is bound to proteoglycans is more susceptible to oxidation, and oxidized LDL is avidly taken up by macrophages or smooth muscle cells, leading to the formation of foam cells. Proteoglycan content differs between atherosclerotic and non-atherosclerotic regions of the artery wall, and apolipoproteins B and E demonstrate striking co-localization with biglycan. However, it is not clear if altered vascular proteoglycan content precedes and contributes to the development of atherosclerosis, or is a consequence of the development of atherosclerosis. The renin angiotensin system (RAS) has been shown to play a critical role in the development of atherosclerosis. Angll, the major biologically active peptide, is clearly pro-atherogenic. Angll increases proteoglycan synthesis, especially up- regulating biglycan. Numerous clinical trials demonstrate that inhibition of the RAS has broad impacts on cardiovascular disease events and risk factors, including decreased risk of death, myocardial infarction, stroke, diabetes mellitus and renal failure. In preliminary studies we show that angll infusion induces increased aortic biglycan content, increased vascular LDL retention, and accelerates atherosclerosis. The overall goal of this grant is to test the hypothesis that induction of biglycan content by angll plays a critical role in the initiation of atherosclerosis. This will be tested in mouse models of atherosclerosis with increased angll levels, and using biglycan deficient mice. A major focus is to identify mechanisms by which angll induces biglycan. The USA has a very high prevalence of atherosclerotic cardiovascular disease. The results of the experiments in this application will establish the role of the response to retention hypothesis in atherosclerosis development, demonstrate a mechanism linking the RAS to atherosclerosis, and identify novel targets for intervention to decrease vascular lipoprotein retention as a strategy to prevent atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Hasan, Ahmed AK
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University of Kentucky
Internal Medicine/Medicine
Schools of Medicine
United States
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Grandoch, Maria; Kohlmorgen, Christina; Melchior-Becker, Ariane et al. (2016) Loss of Biglycan Enhances Thrombin Generation in Apolipoprotein E-Deficient Mice: Implications for Inflammation and Atherosclerosis. Arterioscler Thromb Vasc Biol 36:e41-50
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Hatch, Nicholas W; Srodulski, Sarah J; Chan, Huei-Wei et al. (2012) Endogenous androgen deficiency enhances diet-induced hypercholesterolemia and atherosclerosis in low-density lipoprotein receptor-deficient mice. Gend Med 9:319-28
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Ballinger, Mandy L; Osman, Narin; Hashimura, Kazuhiko et al. (2010) Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo. J Cell Mol Med 14:1408-18
Yang, Sundy N Y; Burch, Micah L; Tannock, Lisa R et al. (2010) Transforming growth factor-? regulation of proteoglycan synthesis in vascular smooth muscle: contribution to lipid binding and accelerated atherosclerosis in diabetes. J Diabetes 2:233-42

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