Cardioprotective Mechanisms of HDL

描述（由申请人提供）：在动脉粥样硬化小鼠模型中，HDL被认为具有动脉粥样硬化保护作用，因为它可以从动脉壁的巨噬细胞中清除过量的胆固醇并抑制炎症。我们已经表明，HDL抑制巨噬细胞中的特定炎症途径-I型干扰素反应途径-这是由TLR 4-TRAM信号调节。我们还证明了人HDL中急性期反应蛋白SAA 1和SAA 2（SAA 1/2）水平升高与巨噬细胞的甾醇流出受损相关。最近的研究表明，人血清HDL的固醇流出能力与CAD状态密切相关，但与HDL-胆固醇和蛋白质（apoA-I）水平无关。因此，血清HDL的胆固醇外排能力可能是一个标记物，也可能是动脉粥样硬化负荷的介导物，它不依赖于HDL-C和apoA-I。HDL蛋白质组的变化可以改变其清除细胞胆固醇或抑制巨噬细胞炎症的能力。因此，我们将测试以下假设：（a）HDL通过抑制TLR 4-TRAM通路来防止巨噬细胞活化和（B）促炎蛋白和抗炎蛋白水平的改变使小鼠和人类中HDL功能障碍。

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.