Abstract 391: Both STAT3 Activation and Cholesterol Efflux Contribute to the Anti-inflammatory Effect of ABCA1/apoa-interaction
Macrophages play a central role in atherogenesis through accumulation of lipids and production of inflammatory cytokines. ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that is essential for HDL synthesis and reverse cholesterol transport, appears to protect against cardiovascular diseases (CVD) by several mechanisms that include removal of cholesterol from arterial wall macrophages and suppression of inflammation. We have shown that in addition to its cholesterol export activity, ABCA1 functions as an anti-inflammatory signaling receptor through activation of the STAT3 pathway independent of its cholesterol export activity. Several studies have suggested that altering cholesterol content of macrophages can affect their inflammatory activities as well. To dissect the role of lipid export and STAT3 activation on the anti-inflammatory effect of apoA-I or its mimetic peptides /ABCA1 interactions, we created an ABCA1 mutant, ABCA1/Y924F-Y1990F with normal lipid export activity but lacking STAT3 activation, and an ABCA1 mutant, ABCA1/W590S, which has normal STAT3 activation capacity but lacking lipid export activity. We transfected ABCA1/WT, ABCA1/Y924F-Y1990F and ABCA1/W590S using lentivirus techniques back into peritoneal macrophages isolated from mice lacking ABCA1. We found that activation of the STAT3 pathway by the apoA-I or its mimetic peptides/ABCA1 interaction without cholesterol efflux is sufficient to significantly decrease inflammatory cytokines expression. Interestedly, increasing cholesterol efflux by the interaction of ABCA1 with apoA-I or its mimetic peptides without STAT3 activation can also decrease the inflammatory response in macrophages. The maximal anti-inflammatory effect of ABCA1/apoA-I interaction appeared only when STAT3 pathway was activated and cholesterol efflux was increased. Taken together, those studies suggest that both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory efflux of ABCA1/apoA-I interaction by in a synergistic manner. Identifying apoA-I mimetic peptides and small molecules to activate both cholesterol efflux and STAT3 may be a new strategy in the development of therapeutic agents that target ABCA1 pathways for treating CVD.
- © 2013 by American Heart Association, Inc.