Recognition of the factors associated with maintaining cholesterol balance may illuminate the pathological mechanisms involved in diseases caused by cholesterol excess, with atherosclerosis the leading example. Homeostatic mechanisms that orchestrate cholesterol balance in the vessel wall and defend against atherosclerosis involve reverse cholesterol transport (RCT) from arterial wall to liver. A central mediator of RCT is the enzyme cholesterol 27-hydroxylase (27-OHase). 27-OHase both facilitates cholesterol transport to the liver and, by generating oxysterol signaling molecules, promotes expression of other RCT proteins, specifically ATP binding cassette transporter 1 (ABCA1). Inflammation is an integral feature of atherosclerosis. The autoimmune disorders systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are characterized by high levels of circulating immune reactants and increased risk of atherosclerosis. We have shown that immune reactants affect cellular cholesterol flux by markedly decreasing 27-OHase and ABCA1 expression. We postulate that, in patients with autoimmune disorders, disruption of cholesterol homeostasis by immune reactants leads to accelerated atherosclerosis. To better understand the immunological mechanisms underlying development of atherosclerosis and to begin to counteract the atherogenic consequences, we propose 4 aims: 1) effect of over- and under- expression of 27-OHase on receptors and transport proteins involved in cholesterol flux, with the addition of a pathophysiologic correlate of atherogenesis: quantitation of foam cell transformation of THP-1 macrophages under the various conditions described; 2) immunomodulatory effects of serum from SLE and RA patients on these cholesterol transport/receptor proteins; 3) mechanisms of up regulation of 27-OHase via adenosine receptor agonists and consequent effects on cholesterol trafficking and 4) therapeutic intervention (statins, adenosine agonists) on cholesterol transport/receptor protein gene expression in a murine model (apolipoprotein E knockout mouse).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073814-03
Application #
7110375
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wassef, Momtaz K
Project Start
2004-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$223,545
Indirect Cost
Name
Winthrop-University Hospital
Department
Type
DUNS #
065937856
City
Mineola
State
NY
Country
United States
Zip Code
11501
Reiss, Allison B; Anwar, Kamran; Merrill, Joan T et al. (2010) Plasma from systemic lupus patients compromises cholesterol homeostasis: a potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease. Rheumatol Int 30:591-8
Reiss, Allison B; Wan, David W; Anwar, Kamran et al. (2009) Enhanced CD36 scavenger receptor expression in THP-1 human monocytes in the presence of lupus plasma: linking autoimmunity and atherosclerosis. Exp Biol Med (Maywood) 234:354-60
Reiss, Allison B; Anwar, Kamran; Wirkowski, Peter (2009) Lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) in atherogenesis: a brief review. Curr Med Chem 16:2641-52
Reiss, Allison B; Carsons, Steven E; Anwar, Kamran et al. (2008) Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 58:3675-83
Reiss, Allison B; Wirkowski, Elzbieta (2007) Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date. Drugs 67:2111-20
Chan, Edwin S L; Zhang, Hongwei; Fernandez, Patricia et al. (2007) Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk. Arthritis Res Ther 9:R4
Reiss, Allison B; Vagell, Michael E (2006) PPARgamma activity in the vessel wall: anti-atherogenic properties. Curr Med Chem 13:3227-38
Reiss, Allison B; Glass, Amy D (2006) Atherosclerosis: immune and inflammatory aspects. J Investig Med 54:123-31
Reiss, Allison B; Edelman, Sari D (2006) Recent insights into the role of prostanoids in atherosclerotic vascular disease. Curr Vasc Pharmacol 4:395-408
Reiss, Allison B; Patel, Chirag A; Rahman, Mohammad M et al. (2004) Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages. Med Sci Monit 10:BR420-5