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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082772-04
Application #
7755006
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2007-02-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$366,250
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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
Thompson, Joel C; Tang, Tao; Wilson, Patricia G et al. (2014) Increased atherosclerosis in mice with increased vascular biglycan content. Atherosclerosis 235:71-5
Tang, Tao; Thompson, Joel C; Wilson, Patricia G et al. (2014) Biglycan deficiency: increased aortic aneurysm formation and lack of atheroprotection. J Mol Cell Cardiol 75:174-80
Tannock, Lisa R (2014) Vascular proteoglycans and atherosclerosis: not over yet. Atherosclerosis 237:435-6
Tang, Tao; Thompson, Joel C; Wilson, Patricia G et al. (2013) Decreased body fat, elevated plasma transforming growth factor-? levels, and impaired BMP4-like signaling in biglycan-deficient mice. Connect Tissue Res 54:5-13
Tang, Tao; Wilson, Patricia G; Thompson, Joel C et al. (2013) Prevention of TGF? induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr-/- mice. J Lipid Res 54:2255-64
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
King, Victoria L; Hatch, Nicholas W; Chan, Huei-Wei et al. (2010) A murine model of obesity with accelerated atherosclerosis. Obesity (Silver Spring) 18:35-41
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

Showing the most recent 10 out of 13 publications