ApoA-I Helical Domains and Cardiovascular Aging

ApoA-I 螺旋结构域与心血管衰老

• 批准号: 6829522
• 负责人: JOHN K BIELICKI
• 金额: $ 7.82万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829522
• 关键词: aging; antiatherogenic agent; antioxidants; apolipoproteins; atherosclerosis; atherosclerotic plaque; cardiovascular function; cell line; cholesterol; clinical research; genetically modified animals; human tissue; immunocytochemistry; inflammation; intermolecular interaction; laboratory mouse; lipid transport; membrane transport proteins; molecular pathology; protein isoforms; protein structure function

DESCRIPTION (provided by applicant): Cardiovascular and Cerebrovascular aging. Aging is associated with the development of atherosclerosis resulting from the deposition of cholesterol in the artery wall and the induction of oxidative events that sustain vascular inflammation. Apolipoprotein (apo) A-I, the major plasma apolipoprotein, is equipped to combat atherosclerosis by mediating the efflux of cholesterol from macrophage foam-cells. The process of cellular cholesterol efflux constitutes the rate-limiting step in the anti-atherogenic reverse cholesterol transport (RCT) pathway. It is not known whether stimulation of RCT is sufficient to attenuate the chronic induction of key mediators that sustain vascular inflammation and atherosclerosis during aging. This issue is important for devising new strategies for the treatment of cardiovascular disease. The development of new therapeutic strategies requires the identification of the helical segments of apoA-I that initiate RCT by mediating cellular cholesterol efflux. Cellular cholesterol efflux mediated by apoA-I is dependent on the ATP-binding cassette transporter A1 (ABCA1) which is down regulated via a degradation pathway. One goal of the proposed studies is to identify the helical structural elements of apoA-I that prevent ABCA1 degradation and mediate cholesterol efflux in an ABCA1-dependent manner. This will be achieved using synthetic peptides based on apoA-I amphipathic or alpha-helices. Recently, a cysteine-bearing variant of apoA-I, i.e. apoA-I(Milano), was found to be a potent inhibitor of lipid peroxidation; thus, the cysteine mutation endows the cholesterol efflux mediating apoA-I with antioxidant capability. The mechanistic basis for the antioxidant activity of apoA-I(Milano) will be elucidated in proposed studies. It is hypothesized that apoA-I(Milano) possesses chain-breaking antioxidant on phospholipid surfaces due to the presence of a free thiol located at the lipid-water interface of an amphipathic alpha-helix. Synthetic peptides that mediate cholesterol efflux and stabilize ABCA1 will be developed with and without apoA-I(Milano)-like antioxidant activity. In vivo studies will be conducted to test whether a peptide with antioxidant activity plus cholesterol efflux-mediating properties is more effective than a peptide that mediates cholesterol efflux alone in preventing the induction of key mediators that sustain vascular inflammation and atherosclemsis in aging mice. These studies are relevant for devising novel strategies to combat cardiovascular aging.

描述（由申请人提供）：心血管和脑血管老化。衰老与胆固醇在动脉壁中的沉积以及维持血管炎症的氧化事件的诱导引起的动脉粥样硬化有关。载脂蛋白（APO）A-I（主要的等离子载脂蛋白）可以通过介导巨噬细胞泡沫细胞的胆固醇外排来对抗动脉粥样硬化。细胞胆固醇外排的过程构成了抗动脉粥样硬化反向胆固醇转运（RCT）途径的速率限制步骤。尚不清楚RCT的刺激是否足以减轻衰老过程中维持血管炎症和动脉粥样硬化的关键介质的慢性诱导。这个问题对于制定治疗心血管疾病的新策略很重要。新的治疗策略的发展需要鉴定通过介导细胞胆固醇外排来启动RCT的ApoA-I的螺旋段。由ApoA-I介导的细胞胆固醇外排取决于ATP结合盒转运蛋白A1（ABCA1），该盒子通过降解途径下降。拟议的研究的一个目标是确定ApoA-I的螺旋结构元素，以防止ABCA1降解并以ABCA1依赖性方式介导胆固醇外排。这将使用基于ApoA-I两亲或α-螺旋的合成肽来实现。最近，发现ApoA-I的半胱氨酸含有变体，即Apoa-I（Milano），是一种有效的脂质过氧化抑制剂。因此，半胱氨酸突变赋予胆固醇外排具有抗氧化能力。拟议的研究将阐明ApoA-I（米兰）抗氧化活性的机械基础。假设ApoA-I（米兰）由于位于两亲α-螺旋体的脂质 - 水界面上的游离硫醇而在磷脂表面上具有链破的抗氧化剂。介导胆固醇外排和稳定的ABCA1的合成肽将在有没有APOA-I（米兰）类似的抗氧化活性的情况下开发。将进行体内研究，以测试具有抗氧化活性和胆固醇液化特性的肽是否比单独介导胆固醇流出的肽更有效，该肽可以仅介导胆固醇外排，从而防止诱导关键的介质，以防止在衰老小鼠中维持血管炎症和动脉粥样硬化。这些研究与制定新型策略来打击心血管衰老。