Apolipoprotein-C Proteoforms in Dyslipidemia and Cardiovascular Disease

载脂蛋白-C 蛋白在血脂异常和心血管疾病中的作用

• 批准号: 10180579
• 负责人: Peter D Reaven
• 金额: $ 39.71万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180579
• 关键词: African American; Ankle; Apolipoproteins; Apolipoproteins C; Atherosclerosis; Binding; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cell Adhesion Molecules; Cessation of life; Clinical; Cohort Studies; Communities; Coronary Arteriosclerosis; Coronary artery; Cross-Sectional Studies; Data; Development; Diabetes Mellitus; Dyslipidemias; Endothelium; Event; Functional disorder; Future; Genes; High Density Lipoproteins; Hydrolysis; Hypertriglyceridemia; Immunoassay; In Vitro; Individual; Inflammatory; Link; Lipids; Lipolysis; Lipoproteins; Low-Density Lipoproteins; Mass Spectrum Analysis; Measures; Mediating; Methods; Multi-Ethnic Study of Atherosclerosis; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pattern; Peripheral arterial disease; Pharmaceutical Preparations; Plasma; Plasma Proteins; Population; Prediabetes syndrome; Production; Prospective Studies; Protein Family; Proteins; Proteoglycan; Race; Risk; Risk Factors; Risk stratification; Role; Sampling; Sialic Acids; Stroke; Testing; Triglyceride Metabolism; Triglycerides; Ultrasonography; Variant; Vascular calcification; Very low density lipoprotein; Veterans; X-Ray Computed Tomography; apolipoprotein C-III; base; blood lipid; cardiovascular disorder risk; cardiovascular risk factor; carotid intima-media thickness; cohort; coronary artery calcium; cytokine; ethnic diversity; follow-up; glucose tolerance; improved; indexing; insight; lipid metabolism; loss of function mutation; monocyte; new therapeutic target; novel; novel therapeutics; particle; prognostic; protein structure; racial and ethnic; racial difference; racial disparity; receptor; secondary analysis; sialylation; targeted treatment; trend; uptake

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.

抽象的 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和 心血管风险。尽管通常将APOC-III测量为总等离子体APOC-III浓度，但它是 在几种翻译后蛋白基质中存在于血液中 - 最丰富的形式包含零， 一两个唾液酸分子。但是，apoc-III蛋白基与模式之间的关系 血脂异常，动脉粥样硬化和心血管疾病（CVD）风险在很大程度上未知。我们发现 较高的相对量的apoc-III与两种唾液酸（但不是0或1）相连 和前瞻性研究，甘油三酸酯水平较低，与CVD风险降低有关 事件。我们的数据还表明，这些蛋白质成型的比率可能随种族和降低脂质疗法而有所不同，并且 APOC-I和C-II的蛋白质类型也表现出与血脂浓度的独特关系。 动脉粥样硬化的多民族研究（MESA）是一项基于社区的大型队列研究CVD风险 因素，动脉粥样硬化的亚临床测量以及主要CVD事件的决定因素。重要的是， 研究中的多样化种族和种族人口将允许对这些蛋白质类型及其进行明确的研究 在探索种族/种族差异的同时，与脂质异常，动脉粥样硬化和CVD事件的关系。 目前的建议将利用新型的质谱免疫测定法（MSIA）来研究 APOC-III（以及第二个APO-CI和C-II）蛋白质相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的发展 梅萨队列中的心血管事件（MACE）。总等离子体APOC-III浓度和APOC-III 在基线和10年随访血浆样品中，MSIA将确定相对蛋白质的量。 AIM 1将检查APOC-III措施与等离子体之间的横截面和纵向关联 脂质。 AIM 2将确定APOC-III是否预测基线动脉粥样硬化和动脉粥样硬化 根据冠状动脉和超声衍生的颈动脉 - 内虫媒体评估的进展 在梅萨期间测量的厚度。 AIM 3将确定APOC-III措施与 事件狼牙棒和总CVD事件。 这将是评估APOC蛋白相和CVD风险之间关系的首次大型研究。作为 现在正在开发疗法以专门针对APOC蛋白来降低甘油三酸酯和CVD风险，A 对APOC蛋白质家族的复杂性和临床意义的更明确的理解是 需要。由于糖尿病和降脂疗法似乎对APOC蛋白质成型有不同的影响，因此 针对特定蛋白质成型和/或个体的子集的靶向治疗可能是有益的。正如我们所拥有的 证明还有许多其他血浆蛋白的蛋白质类型，这项研究也可能有助于强调 鉴定翻译后蛋白质结构及其功能差异的变化的更广泛价值。