Cardioprotective Mechanisms of HDL

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DESCRIPTION (provided by applicant): In mouse models of atherosclerosis, HDL is thought to be atheroprotective because it removes excess cholesterol from macrophages of the artery wall and inhibits inflammation. We have shown that HDL inhibits a specific inflammatory pathway in macrophages - the type I interferon response pathway - that is regulated by TLR4-TRAM signaling. We also have demonstrated that elevated levels of the acute-phase response proteins SAA1 and SAA2 (SAA1/2) in human HDL associate with impaired sterol efflux from macrophages. Recent studies demonstrate that the sterol efflux capacity of human serum HDL strongly associates with CAD status but is independent of HDL-cholesterol and protein (apoA-I) levels. Thus, the cholesterol efflux capacity of serum HDL might be a marker-and perhaps mediator-of atherosclerotic burden that is independent of HDL- C and apoA-I. Changes in the HDL proteome could alter its ability to remove cellular cholesterol or inhibit macrophage inflammation. We therefore will test the hypotheses that (a) HDL prevents macrophage activation by inhibiting the TLR4-TRAM pathway and (b) altered levels of pro- and anti-inflammatory proteins render HDL dysfunctional in mice and humans.