Cardioprotective Mechanisms of HDL

描述(申请人提供)：在动脉粥样硬化的小鼠模型中，高密度脂蛋白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多余的胆固醇，并抑制炎症。我们已经证明，高密度脂蛋白抑制巨噬细胞中一种特定的炎症途径--I型干扰素反应途径--该途径受TLR4-TRAM信号调节。我们还证明，人类高密度脂蛋白中急性时相反应蛋白SAA1和SAA2(SAA1/2)水平的升高与巨噬细胞的类固醇外流受损有关。最近的研究表明，人血清高密度脂蛋白的甾醇外排能力与冠心病状态密切相关，但与高密度脂蛋白、胆固醇和蛋白质(apoA-I)水平无关。因此，血清高密度脂蛋白的胆固醇流出能力可能是动脉粥样硬化负担的一个标志，也可能是一个中介，该负荷独立于高密度脂蛋白和载脂蛋白A-I。高密度脂蛋白蛋白质组的变化可能会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)高密度脂蛋白通过抑制TLR4-TRAM途径来阻止巨噬细胞的激活，以及(B)致炎和抗炎蛋白水平的改变使高密度脂蛋白在小鼠和人类中功能失调。

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.