This is a revised application, for which we have now developed the mice that were requested in the previous reviews: floxed angiotensinogen and AT1a receptors. Therefore, all the critical reagents to the proposed studies are now available. Evidence has evolved, primarily in the last decade, demonstrating that the renin angiotensin system (RAS) has a profound effect on atherogenic mechanisms. However, many questions remain regarding the origin of the bioactive peptides and the mechanisms of the effects. Based on the findings of the previously funded period and others, the focus of the proposed research is to determine the relative importance of the systemic versus local RAS to the development of atherosclerosis. The central hypothesis of this proposal is that macrophage-derived RAS components are responsible for the local generation of angiotensin peptides that propagate atherosclerosis primarily via stimulation of AT1a receptors expressed on endothelial cells. To determine the validity of this hypothesis, the following specific aims are proposed.
Aim 1 : Determine the contribution of angiotensinogen from the liver (systemic) versus macrophages (local) to lesion size and characteristics of hypercholesterolemia-induced atherosclerosis.
Aim 2 : Determine the contribution of ACE1 and ACE2 expression on bone marrow-derived cells to the development of atherosclerotic lesion size and characteristics.
Aim 3 : Determine the cellular location of AT1a receptor expression that influences the atherogenic process.

Public Health Relevance

Atherosclerotic diseases are the major cause of morbidity and mortality in the US population. Therefore, investigations to prevent these diseases have vast public health implications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062846-07
Application #
7991774
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Thrasher, Terry N
Project Start
2000-09-20
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
7
Fiscal Year
2011
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
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Lu, Hong; Wu, Congqing; Howatt, Deborah A et al. (2016) Angiotensinogen Exerts Effects Independent of Angiotensin II. Arterioscler Thromb Vasc Biol 36:256-65
Wu, Congqing; Xu, Yinchuan; Lu, Hong et al. (2015) Cys18-Cys137 disulfide bond in mouse angiotensinogen does not affect AngII-dependent functions in vivo. Hypertension 65:800-5
Davis, Frank; Rateri, Debra L; Daugherty, Alan (2014) Aortic aneurysms in Loeys-Dietz syndrome - a tale of two pathways? J Clin Invest 124:79-81
Thatcher, Sean E; Zhang, Xuan; Howatt, Deborah A et al. (2014) Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 34:2617-23
Davis, Frank M; Rateri, Debra L; Daugherty, Alan (2014) Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies. Heart 100:1498-505
Chen, Xiaofeng; Lu, Hong; Zhao, Mingming et al. (2013) Contributions of leukocyte angiotensin-converting enzyme to development of atherosclerosis. Arterioscler Thromb Vasc Biol 33:2075-80
Lu, Hong; Daugherty, Alan (2013) Atherosclerosis: cell biology and lipoproteins. Curr Opin Lipidol 24:455-6
Lu, Hong; Wu, Congqing; Howatt, Deborah A et al. (2013) Differential effects of dietary sodium intake on blood pressure and atherosclerosis in hypercholesterolemic mice. J Nutr Biochem 24:49-53
Lu, Hong; Daugherty, Alan (2013) Atherosclerosis: cell biology and lipoproteins. Curr Opin Lipidol 24:107-8

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