Cholesterol accumulation in arterial wall macrophages and inflammation of artery wall both contribute to the development of cardiovascular disease (CVD). ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that is essential for HDL synthesis and reversal cholesterol transport, appears to protect against CVD by several mechanisms that include removal of cholesterol from arterial wall cells and suppression of inflammation. We have shown that Janus kinase 2 (JAK2) activation regulates ABCA1- mediated cholesterol and phospholipids efflux by affecting the interaction of apoA1 or apoA-I mimetic peptides with ABCA1. However the mechanisms by which JAK2 activation regulates ABCA1 binding to apoA-I is unknown. Moreover, we also found that the interaction of apoA-I or apolipoprotein-mimetic peptides with ABCA1 activates STAT3 pathway. Whereas JAK2 activation is required for the lipid-removal and optimum apoA-I binding activity of ABCA1, STAT3 activation is not involved in lipid transport. It has been shown that constitutive activation of STAT3 in macrophages suppresses production of inflammatory cytokines, implying that factors that activate STAT3 in macrophages have an anti-inflammatory effect. Indeed, we found that pre- treating ABCA1-expressing J774 macrophages with apoA-I or its mimetic peptides activate STAT3 and markedly reduce subsequent LPS or lipid A-stimulated cytokine production. We hypothesize that, in addition to its cholesterol export activity, which may have anti-inflammatory effects, ABCA1 also functions as an anti- inflammatory signaling receptor through the activation of STAT3 pathway independent of its lipid export activity. This project will answer several key questions: 1. How will JAK2 activation affect apoA-I or its mimetic peptides interaction with ABCA1, therefore to regulate ABCA1-mediated cholesterol efflux? 2: Is STAT3 activation without cholesterol efflux sufficient to mediate the anti-inflammatory effect of the interaction of ABCA1 with apoA-I or apoA-I mimetic peptides? 3: Will apoA-I mimetic peptides that have greater and more specific activity in activating the ABCA1/JAK2/STAT3 pathways are superior at mediating the cholesterol efflux and anti-inflammatory effects of ABCA1? Address those questions would significantly advance our knowledge on ABCA1-mediated cholesterol efflux and could open new opportunities in the development of therapeutic agents that target ABCA1 pathways for treating CVD

Public Health Relevance

ATP-binding cassette transporter A1 (ABCA1), a membrane protein essential for high density apolipoprotein (HDL) synthesis and reversal cholesterol transport, appears to protect against cardiovascular diseases (CVD) by several mechanisms that include removal of cholesterol from arterial wall cells and suppression of inflammation. It is therefore vital to increase our understanding of how ABCA1 mediates cholesterol transport and suppresses inflammation. The major goal of this proposal is to determine how signaling pathways regulate the cholesterol export and the anti-inflammatory activities mediated by the interactions of ABCA1 with apoA-I and its mimetic peptides.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121214-01
Application #
8610671
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2014-01-03
Project End
2018-12-31
Budget Start
2014-01-03
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$391,500
Indirect Cost
$166,500
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195