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巨噬细胞中去除多余的胆固醇并抑制炎症。我们已经证明HDL抑制巨噬细胞中特定的炎症途径-由TLR4-TRAM信号调节的I型干扰素反应途径。我们还证明，人HDL中急性期反应蛋白SAA1和SAA2 （SAA1/2）水平升高与巨噬细胞的固醇外排受损有关。最近的研究表明，人血清HDL的固醇外排能力与CAD状态密切相关，但与HDL-胆固醇和蛋白（apoA-I）水平无关。因此，血清HDL的胆固醇外排能力可能是独立于HDL- C和apoA-I的动脉粥样硬化负荷的标志物，也可能是介质。高密度脂蛋白蛋白质组的改变可能改变其去除细胞胆固醇或抑制巨噬细胞炎症的能力。因此，我们将验证以下假设：(a) HDL通过抑制TLR4-TRAM途径阻止巨噬细胞活化；(b)在小鼠和人类中，促炎性和抗炎蛋白水平的改变导致HDL功能失调。

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.