High density lipoprotein (HDL) plays a major role in cholesterol homeostasis and atherosclerosis. Yet our understanding of its structure, interactions with HDL-associated proteins, and alterations in function during atherosclerosis, remain poorly understood. We propose to use a multidisciplinary approach to better understand how distinct structural elements of HDL facilitate specific biological functions in reverse cholesterol transport (ROT) and may become """"""""dysfunctional"""""""" through site-specific oxidative modification within human atherosclerotic plaque. We have developed novel tools for structurally, functionally and clinically characterizing dysfunctional forms of HDL and their involvement in human disease. We will employ these to achieve our overall major goals of: (i) defining HDL function and site-specific oxidative modifications within human atherosclerotic plaque that adversely impact upon normal lipoprotein function; and (ii) exploring the clinical utility of quantifying specific """"""""dysfunctional"""""""" HDL forms in human clinical studies. We will achieve this with the following specific aims:
Aim 1) To define important structural elements critical for nascent HDL particle interaction with LOAT and maturation into a cholesterol-ester laden spheroidal form, and to test the hypothesis that site-specific oxidative modifications of apoAl Tyr166, a known functional residue in the LOAT interaction site modified within human atherosclerotic plaque, generates both a """"""""dysfunctional"""""""" form of HDL and identifies individuals at increased risk for atherosclerotic heart disease.
Aim 2) To discover the structural modification induced by MPO-catalyzed oxidation on apoA1 of HDL that converts the particle into a pro-inflammatory form and to test the hypothesis that MPO-specific oxidative modification of HDL identifies individuals at increased risk for atherosclerotic heart disease. Collectively, the proposed studies represent an innovative and multidisciplinary approach designed to elaborate key structural elements of HDL that support specific atheroprotective functions and how site specific oxidative modifications to specific residues in vivo adversely impacts upon normal lipoprotein function and generate distinct """"""""dysfunctional"""""""" HDL forms of potential clinical prognostic utility.

Public Health Relevance

The proposed studies will provide new insights into how specific structural features of high density lipoprotein (HDL) contribute to its normal biological functions in reverse cholesterol transport. They also explore the role of structurally distinct site-specific oxidative modifications to apoAl of HDL in altered athero-protective functions of the lipoprotein in humans. The studies will help identify new diagnostic tests for heart disease risk prediction, and potential therapeutic targets for treatment and prevention of heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Cleveland Clinic Lerner
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Rahman, Karishma; Fisher, Edward A (2018) Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression. Front Cardiovasc Med 5:32
Senthong, Vichai; Hudec, Timothy; Neale, Sarah et al. (2017) Relation of Red Cell Distribution Width to Left Ventricular End-Diastolic Pressure and Mortality in Patients With and Without Heart Failure. Am J Cardiol 119:1421-1427
Senthong, Vichai; Wu, Yuping; Hazen, Stanley L et al. (2017) Predicting long-term prognosis in stable peripheral artery disease with baseline functional capacity estimated by the Duke Activity Status Index. Am Heart J 184:17-25
Tang, W H Wilson; Wang, Zeneng; Li, Xinmin S et al. (2017) Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem 63:297-306
Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius et al. (2017) Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol 5:534-543
Hammadah, Muhammad; Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V et al. (2017) High-density lipoprotein-associated paraoxonase-1 activity for prediction of adverse outcomes in outpatients with chronic heart failure. Eur J Heart Fail 19:748-755
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Hartiala, Jaana; Breton, Carrie V; Tang, W H Wilson et al. (2016) Ambient Air Pollution Is Associated With the Severity of Coronary Atherosclerosis and Incident Myocardial Infarction in Patients Undergoing Elective Cardiac Evaluation. J Am Heart Assoc 5:
Hartiala, Jaana A; Tang, W H Wilson; Wang, Zeneng et al. (2016) Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease. Nat Commun 7:10558
Iqbal, Asif J; Fisher, Edward A; Greaves, David R (2016) Inflammation-a Critical Appreciation of the Role of Myeloid Cells. Microbiol Spectr 4:

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