Inflammation and lipid accumulation in the vascular wall constitute critical events in initiation and progression of cardiovascular disease, manifested in myocardial infarction and stroke in more than a half of the US population. Activated endothelial cells (EC) secrete chemokines and express adhesion molecules to recruit leukocytes to the vascular wall. Oxidized LDL and dysfunctional HDL play a major role in EC-mediated inflammation, whereas functional HDL preserves the EC integrity and prevents inflammatory responses. One of the major mechanisms by which HDL exerts its protective function is cholesterol efflux from the plasma membrane of EC. We discovered that apoA-I binding protein (AIBP) significantly improves HDL function by accelerating cholesterol efflux from EC. AIBP is a secreted protein and its effect on EC is paracrine and non-cell autonomous. These findings open the possibility of using AIBP or AIBP-derived peptides as a therapy to improve the cholesterol efflux function of HDL and thereby prevent and/or reverse vascular pathology. Here we propose to test the hypothesis that AIBP reduces EC inflammatory responses via modulation of cholesterol efflux and lipid rafts. We will test this hypothesis in cellular models as well as in aorta explants, by measuring expression of cytokines and adhesion molecules, probing relevant signaling pathways, detecting ROS, apoptosis and autophagy, and assessing LDL transcytosis and monocyte adhesion. Further, we will determine effects of systemic and tissue-specific AIBP deficiency on endothelial function. We have developed Aibp LoxP and Aibp knockout mice, which are viable and fertile. AIBP expression has been detected in macrophages and vascular smooth muscle cells (VSMC) of mouse atherosclerotic lesions. Thus, we propose that AIBP secreted by macrophages and/or VSMC protects aortic EC and that deletion of Aibp in these cells will lead to exacerbated EC inflammatory responses and increased atherosclerosis burden. We also hypothesize that, conversely, raising AIBP levels will improve endothelial function and reduce inflammation. The hypothesis will be tested in vivo with mouse and zebrafish animal models and ex vivo with human plasma samples obtained from patients with dyslipidemia and/or cardiovascular disease (CVD). In a hypercholesterolemic zebrafish model, we expect that conditional expression of Aibp will reduce vascular lipid accumulation, foam cell formation, membrane lipid order in EC, and vascular permeability. In a hypercholesterolemic mouse model, we expect that infusion of recombinant AIBP, alone or in combination with apoA-I, will reduce EC inflammation and atherosclerosis. In addition, human plasma and HDL isolated from CVD patients will be supplemented with recombinant AIBP and tested for their effect on monocyte adhesion to EC. We expect that AIBP will improve protective properties of dysfunctional HDL. Results of these experiments, if positive, will facilitate future development of AIBP-based therapeutic applications.

Public Health Relevance

Maintaining normal function of endothelial cells, which cover the surface of the vascular wall, is important for prevention and reversal of atherosclerosis and cardiovascular disease, the major cause of mortality and morbidity in the United States. We have discovered that apoA-I binding protein (AIBP) helps remove cholesterol from endothelial cells and restrict their inflammatory activation. This project will test the hypothesis that raisin AIBP levels will diminish endothelial dysfunction during development of atherosclerosis, the approach that may results in a new therapy for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL124174-01A1
Application #
8885205
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Hasan, Ahmed AK
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$515,635
Indirect Cost
$175,586
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Miller, Yury I; Shyy, John Y-J (2017) Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation. Trends Endocrinol Metab 28:143-152
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
Yeang, Calvin; Gordts, Philip L S M; Tsimikas, Sotirios (2017) Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. Circ Res 120:1050-1052
Pechlaner, Raimund; Tsimikas, Sotirios; Yin, Xiaoke et al. (2017) Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol 69:789-800
Choi, Soo-Ho; Sviridov, Dmitri; Miller, Yury I (2017) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta 1862:393-397
van Capelleveen, Julian C; Bernelot Moens, Sophie J; Yang, Xiaohong et al. (2017) Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 37:1206-1212
Liu, Chao; Gaudet, Daniel; Miller, Yury I (2017) Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients. PLoS One 12:e0169939
Yeang, Calvin; Cotter, Bruno; Tsimikas, Sotirios (2016) Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis. Cardiovasc Drugs Ther 30:75-85
Yang, Xiaohong; Lee, Sang-Rok; Choi, Yun-Seok et al. (2016) Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results. J Lipid Res 57:706-13
Verbeek, Rutger; Boekholdt, S Matthijs; Stoekenbroek, Robert M et al. (2016) Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study. J Lipid Res 57:697-705

Showing the most recent 10 out of 14 publications