The association of SAA with apoB lipoproteins affects cardiovascular risk

描述(由申请人提供)： 心血管疾病(CVD)是发达国家发病率和死亡率的主要原因，也是退伍军人的主要健康问题。尽管有许多针对CVD危险因素的药物，但对高危个体的识别仍然不完整。此外，仍有必要确定新的治疗目标。SAA是一种急性期反应物，在糖尿病、代谢综合征(METS)或类风湿性关节炎等慢性炎症性疾病中显著且持续升高，这些疾病都与心血管疾病的发病率增加有关。已发现SAA可预测CVD事件。此外，我们和其他人最近在小鼠模型中表明，增加SAA直接导致动脉粥样硬化。正如在动脉粥样硬化的滞留假说的反应中所描述的那样，血管壁蛋白多糖对致动脉粥样硬化脂蛋白的内皮下滞留启动了动脉粥样硬化。虽然在健康状态下，SAA只与高密度脂蛋白相关，但我们和其他人之前已经在糖尿病和/或肥胖的小鼠模型中报道了SAA与含apoB的脂蛋白相关，我们最近在人类研究中证实了这一观察结果。在初步研究中，我们证明了胰岛素抵抗状态下SAA与含载脂蛋白B的脂蛋白的相关性增加，这可能是由于胰岛素抵抗时脂蛋白清除延迟所致。在新的初步研究中，我们证明了SAA可以从高密度脂蛋白转变为含载脂蛋白B的脂蛋白。SAA本身具有蛋白多糖结合特性，我们的初步数据表明，SAA在载脂蛋白B上的存在增强了它们的保留力。这项资助的中心假设是SAA从高密度脂蛋白转变为含载脂蛋白B的脂蛋白是促进动脉粥样硬化的。我们认为，在胰岛素抵抗的情况下，如蛋氨酸和糖尿病，载脂蛋白B上SAA的存在有助于在这些人群中观察到动脉粥样硬化和心血管疾病的增加。利用体外、体内和临床研究，这项建议的结果将确定SAA增强载脂蛋白的动脉粥样硬化，从而可能确定SAA作为治疗干预的靶点。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed nations and is a major health issue in Veterans. Despite numerous pharmacological agents targeting CVD risk factors, the identification of individuals at high risk remains incomplete. Further, there is still a need to identify new targets for therapy. SAA is an acute phase reactant that is significantly and persistently elevated in chronic inflammatory conditions such as diabetes, metabolic syndrome (MetS) or rheumatoid arthritis, which are all associated with increased rates of CVD. SAA has been found to be predictive of CVD events. Furthermore, we and others have recently shown in murine models that increased SAA is directly pro-atherogenic. As described in the Response to Retention hypothesis of atherosclerosis, the sub-endothelial retention of atherogenic lipoproteins by vascular wall proteoglycans initiates atherosclerosis. Although in the healthy state SAA is exclusively associated with HDL, we and others have previously reported SAA in association with apoB-containing lipoproteins in murine models of diabetes and/or obesity and we recently confirmed this observation in human studies. In preliminary studies we demonstrate increased association of SAA with apoB- containing lipoproteins in insulin resistant states, which may be due to the delayed lipoprotein clearance seen with insulin resistance. In new preliminary studies we demonstrate that SAA can shift from HDL to apoB-containing lipoproteins. SAA itself has proteoglycan binding properties and our preliminary data demonstrates that the presence of SAA on apoB-lipoproteins enhances their retention. The central hypothesis of this grant is that the shift of SAA from HDL to apoB-containing lipoproteins is pro-atherogenic. We propose that the presence of SAA on apoB- containing lipoproteins in insulin resistant conditions such as MetS and diabetes contributes to the increased atherosclerosis and CVD observed in these populations. Using in vitro, in vivo, and clinical studies, the results of this proposal will identify that SAA augments the atherogenicity of apoB lipoproteins and thus may identify SAA as a target for therapeutic intervention.