The association of SAA with apoB lipoproteins affects cardiovascular risk

SAA 与 apoB 脂蛋白的关联影响心血管风险

• 批准号: 8967203
• 负责人: LISA R TANNOCK
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967203
• 关键词: Acute-Phase Proteins; Affect; Affinity; Apolipoproteins B; Atherosclerosis; Binding; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cause of Death; Chronic; Clinical Research; Data; Developed Countries; Development; Diabetes Mellitus; Dyslipidemias; Event; Fatty acid glycerol esters; Grant; Health; High Density Lipoproteins; Human; In Vitro; Individual; Inflammatory; Insulin Resistance; Lipase; Lipids; Lipoproteins; Literature; Low-Density Lipoproteins; Metabolic syndrome; Morbidity - disease rate; Mus; Obesity; Outcome; Population; Property; Proteins; Proteoglycan; Publishing; Reporting; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Serum amyloid A protein; Testing; Therapeutic Intervention; Time; Vascular remodeling; Very low density lipoprotein; Veterans; base; cardiovascular disorder risk; cardiovascular risk factor; drinking; high risk; in vivo; inflammatory marker; insulin sensitivity; intravenous glucose tolerance test; mortality; mouse model; new therapeutic target; novel; overexpression; particle; response; targeted agent; targeted treatment; therapeutic target

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.

描述（由申请人提供）： 心血管疾病（CVD）是发达国家发病和死亡的主要原因，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，但对高风险个体的识别仍然不完整。此外，仍然需要确定新的治疗靶点。 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着且持续升高，这些疾病都与 CVD 发病率增加有关。 SAA 被发现可以预测 CVD 事件。此外，我们和其他人最近在小鼠模型中表明，SAA 的增加直接导致动脉粥样硬化。正如动脉粥样硬化滞留假说中所述，血管壁蛋白多糖将致动脉粥样化脂蛋白在内皮下滞留，引发动脉粥样硬化。尽管在健康状态下，SAA 完全与 HDL 相关，但我们和其他人之前曾报道过，在糖尿病和/或肥胖的小鼠模型中，SAA 与含 apoB 的脂蛋白相关，并且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，我们证明在胰岛素抵抗状态下，SAA 与含 apoB 的脂蛋白的关联性增强，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 SAA 可以从 HDL 转变为含有 apoB 的脂蛋白。 SAA 本身具有蛋白聚糖结合特性，我们的初步数据表明，apoB 脂蛋白上 SAA 的存在增强了它们的保留。这项资助的中心假设是 SAA 从 HDL 到含 apoB 的脂蛋白的转变是促动脉粥样硬化的。我们认为，在 MetS 和糖尿病等胰岛素抵抗疾病中，含 apoB 脂蛋白上 SAA 的存在会导致这些人群中观察到的动脉粥样硬化和 CVD 增加。通过体外、体内和临床研究，该提案的结果将确定 SAA 增强 apoB 脂蛋白的致动脉粥样硬化性，从而可能将 SAA 确定为治疗干预的目标。