Apolipoprotein-C Proteoforms in Dyslipidemia and Cardiovascular Disease

摘要 载脂蛋白C-III（apoC-III）越来越被认为是血脂异常的重要决定因素， 心血管风险虽然apoC-III通常测量为总血浆apoC-III浓度，但它是 以几种翻译后蛋白形式存在于血液中-最丰富的形式含有零， 一个或两个唾液酸分子然而，apoC-III蛋白质型和蛋白质表达模式之间的关系尚不清楚。 血脂异常、动脉粥样硬化和心血管疾病（CVD）风险在很大程度上是未知的。我们发现 较高相对量的apoC-III与两个唾液酸（但不是0或1）在横截面中连接， 和前瞻性研究，甘油三酯水平较低，并与心血管疾病风险降低相关 事件我们的数据还表明，这些蛋白形式的比例可能会因种族和降脂治疗而异， apoC-I和C-II的蛋白形式也显示出与血脂浓度的独特关系。 多种族动脉粥样硬化研究（梅萨）是一项大型的基于社区的CVD风险队列研究 动脉粥样硬化的亚临床指标和主要CVD事件的决定因素。重要的是 研究中不同的种族和人种群体将允许对这些蛋白质型及其 与血脂异常、动脉粥样硬化和CVD事件的关系，同时探索种族/种族差异。 本提案将利用一种新的质谱免疫分析（MSIA）来研究 apoC-III（其次是apo-CI和C-II）蛋白质型与血浆脂质浓度的关系， 血管钙化和颈动脉粥样硬化的进展，以及主要不良反应的发生， 梅萨队列中的心血管事件（MACE）。总血浆apoC-III浓度和apoC-III 将通过MSIA测定基线和10年随访血浆样品中的相对蛋白形式量。 目的1将研究apoC-III测量和血浆中apoC-III浓度之间的横向和纵向关联。 脂质。目的2将确定apoC-III指标是否可预测基线动脉粥样硬化和动脉粥样硬化 根据冠状动脉CT扫描和超声检查衍生的颈动脉-内膜-中膜评价进展 在梅萨期间测量的厚度。目标3将确定apoC-III指标与 MACE事件和总CVD事件。 这将是第一个评估apoC蛋白质型与CVD风险之间关系的大型研究。作为 目前正在开发专门针对apoC蛋白的治疗方法，以降低甘油三酯和CVD风险， 对apoC家族蛋白质的复杂性和临床意义的更明确的理解是 needed.由于糖尿病和降脂治疗似乎对apoC蛋白质型有不同的影响， 将治疗靶向于特定的蛋白质型和/或个体亚群可能是有益的。正如我们 证明有许多其他血浆蛋白的蛋白形式，这项研究也可能有助于强调 鉴定翻译后蛋白质结构变异及其功能差异的更广泛价值。

Abstract Apolipoprotein C-III (apoC-III) is increasingly recognized as an important determinant of dyslipidemia and cardiovascular risk. Although apoC-III is typically measured as total plasma apoC-III concentration, it is present in blood in several post-translational proteoforms - with the most abundant forms containing zero, one or two sialic acid molecules. However, the relationships between apoC-III proteoforms and patterns of dyslipidemia, atherosclerosis and cardiovascular disease (CVD) risk are largely unknown. We found that higher relative amounts of apoC-III with two sialic acids (but not 0 or 1) were linked in cross-sectional and prospective studies with lower triglyceride levels, and were associated with reduced risk for CVD events. Our data also indicate ratios of these proteoforms may vary with race and lipid-lowering therapies and that proteoforms of both apoC-I and C-II also demonstrate unique relationships with blood lipid concentrations. The Multi-Ethnic Study of Atherosclerosis (MESA) is a large community based cohort study of CVD risk factors, subclinical measures of atherosclerosis and determinants of major CVD events. Importantly, the diverse ethnic and racial population within the study will permit a definitive study of these proteoforms and their relationships with lipid abnormalities, atherosclerosis and CVD events while exploring ethnic/racial differences. The present proposal will utilize a novel mass spectrometry immunoassay (MSIA) to investigate the relationships of apoC-III (and secondarily apo-CI and C-II) proteoforms with plasma lipid concentrations, progression of vascular calcification and carotid atherosclerosis, and development of major adverse cardiovascular events (MACE) within the MESA cohort. Total plasma apoC-III concentrations and apoC-III relative proteoform amounts will be determined by MSIA in baseline and 10-year follow-up plasma samples. Aim 1 will examine the cross-sectional and longitudinal associations between apoC-III measures and plasma lipids. Aim 2 will determine whether apoC-III measures predict baseline atherosclerosis and atherosclerosis progression evaluated from CT scans of coronary arteries and ultrasonography-derived carotid-intima-media thickness measured during MESA. Aim 3 will determine the relationship between apoC-III measures and incident MACE and total CVD events. This will be the first large study evaluating relationships between apoC proteoforms and CVD risk. As therapies are now being developed to specifically target apoC proteins to reduce triglycerides and CVD risk, a more definitive understanding of the complexity and clinical implications of the apoC family of proteins is needed. As diabetes and lipid-lowering therapies appear to have differential effects on apoC proteoforms, targeting therapy to specific proteoforms and/or subsets of individuals may be beneficial. As we have demonstrated that there are proteoforms of many other plasma proteins, this study may also help highlight the broader value of identifying variations in post-translational protein structure and their functional differences.