Apolipoprotein-C Proteoforms in Dyslipidemia and Cardiovascular Disease

摘要 载脂蛋白C-III(apoC-III)日益被认为是血脂异常的重要决定因素。 心血管风险。虽然apoC-III通常以血浆总apoC-III浓度来测量，但它是 在血液中以几种翻译后蛋白质形式存在--其中最丰富的形式包含零， 一个或两个唾液酸分子。然而，载脂蛋白C-III蛋白形式与血管紧张素转换酶模式之间的关系 血脂异常、动脉粥样硬化和心血管疾病(CVD)的风险在很大程度上是未知的。我们发现 较高的载脂蛋白C-III与两个唾液酸(而不是0或1)的相对量在横截面上相连 以及甘油三酯水平较低的前瞻性研究，并与降低心血管疾病的风险有关 事件。我们的数据还表明，这些蛋白形式的比例可能会随着种族和降脂疗法的不同而不同 载脂蛋白C-I和C-II的蛋白形式也显示出与血脂浓度的独特关系。 动脉粥样硬化的多种族研究(MESA)是一项基于社区的心血管疾病风险的大型队列研究 动脉粥样硬化的因素、亚临床测量和主要心血管事件的决定因素。重要的是， 这项研究中不同的种族和种族群体将允许对这些蛋白质形式及其 在探索民族/种族差异的同时，研究与血脂异常、动脉粥样硬化和心血管事件的关系。 本提案将利用一种新的质谱学免疫分析(MSIA)来研究 载脂蛋白C-III(以及继发的载脂蛋白-CI和C-II)与血脂浓度的关系 血管钙化与颈动脉粥样硬化的进展及主要不利因素的发展 MESA队列中的心血管事件(MACE)。血浆总载脂蛋白C-III浓度与载脂蛋白C-III 相对蛋白样量将由MSIA在基线和10年后的血浆样本中测定。 目标1将检查载脂蛋白C-III指标和血浆之间的横截面和纵向关联 脂类。目标2将确定载脂蛋白C-III测量是否可以预测基线动脉粥样硬化和动脉粥样硬化 根据冠状动脉CT扫描和超声检测颈动脉内膜中层评估进展 在台面上测量的厚度。目标3将确定载脂蛋白C-III措施与 事件Mace和CVD事件总数。 这将是评估载脂蛋白C蛋白形式和心血管疾病风险之间关系的第一项大型研究。AS 目前正在开发专门针对载脂蛋白C蛋白的治疗方法，以降低甘油三酯和心血管疾病的风险。 对载脂蛋白C家族的复杂性和临床意义的更明确的理解是 需要的。由于糖尿病和降脂疗法似乎对载脂蛋白C蛋白有不同的影响， 针对特定蛋白形式和/或个体亚群的靶向治疗可能是有益的。正如我们所做的那样 证明了存在许多其他血浆蛋白的蛋白质形式，这项研究也可能有助于突出 识别翻译后蛋白质结构的变异及其功能差异具有更广泛的价值。

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.