High levels of high density lipoprotein (HDL)-cholesterol are associated with lowered risk for cardiovascular disease. Although several mechanisms may play a role in HDL's protective effect, HDL and apolipoprotein-AI (apoAl), the major protein constituent of HDL, are major components of the reverse cholesterol transport pathway, in which cholesterol is removed from the periphery and transferred to the liver for excretion. In the first step of the reverse cholesterol transport pathway, apoAl acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCAl, generating nascent HDL. Although this step in the pathway has been under intensive investigation, we still know very little about the molecular details of the ABCAl mediated assembly of cellular lipids on apoAI. Not all HDL is equivalent, and several studies have reported that individuals with coronary artery disease have HDL that is dysfunctional. We recently created an apoAl variant that is resistant to becoming dysfunctional. We propose to follow up on the mechanism of apoAl lipidation and reverse cholesterol transport in two specific aims.
Aim 1 will address mechanisms of both cell-free and cellular lipidation of apoAl using biophysical, biochemical, and genetic approaches.
Aim 2 will address the role of apoAl modification on in vivo reverse cholesterol transport and atherosclerosis lesion regression. We will explore the effects of inflammation on reverse cholesterol transport and apoAl modification, and we will determine if our novel apoAl variant is superior to wild type apoAl in mediating reverse cholesterol transport and lesion regression in several mouse models. In other words, we hope the discoveries we make will allow us to make """"""""good cholesterol"""""""" even better.

Public Health Relevance

HDL is normally protective against atherosclerosis;however, HDL can become dysfunctional and lose its protective properties. The proposed studies will determine the efficacy of an oxidant resistant form of apoAl to prevent HDL dysfunction. These studies may lead to a better understanding of apoAl and HDL function, and provide preclinical evidence for the use of an oxidant resistant apoAl variant to treat atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL098055-02
Application #
8266503
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$506,385
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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
Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35
Iqbal, Asif J; Barrett, Tessa J; Taylor, Lewis et al. (2016) Acute exposure to apolipoprotein A1 inhibits macrophage chemotaxis in vitro and monocyte recruitment in vivo. Elife 5:
Gulshan, Kailash; Brubaker, Gregory; Conger, Heather et al. (2016) PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. Circ Res 119:827-38
Hammadah, Muhammad; Georgiopoulou, Vasiliki V; Kalogeropoulos, Andreas P et al. (2016) Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure. Circ Heart Fail 9:e002115

Showing the most recent 10 out of 141 publications