Iron-Mediated Cardiovascular Injury

铁介导的心血管损伤

• 批准号: 6577514
• 负责人: LAWRENCE HORWITZ
• 金额: $ 33.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577514
• 关键词: cardiolipins; cardiovascular injury; cell cycle; chelating agents; chelation therapy; chemoprevention; cyclic peptides; cytoprotection; heart function; heat shock proteins; hypoxia inducible factor 1; iron metabolism; iron poisoning; laboratory mouse; laboratory rat; mitochondria; nonhuman therapy evaluation; nuclear factor kappa beta; oxidative stress; protein kinase C; superoxide dismutase; swine; tissue /cell culture; vascular endothelial growth factors

DESCRIPTION (provided by applicant): We propose that iron plays a critical role in adverse processes of importance in vascular and myocardial injury. Iron-mediated redox signaling may regulate growth factors and cell cycle progression leading to restenosis after vascular injury. Excessive iron overload leads to cardiac dysfunction. To study these issues we will employ a novel lipid-soluble iron chelator that rapidly enters cells and is far more effective in preventing iron-mediated reactions than chelators available heretofore. In AIM 1 we will study, in cultured human vascular smooth muscle and endothelial cells, the role of iron-mediated redox signaling on transcriptional activation of nuclear factor-kappa B, activator protein-1 and hypoxia-inducible factor (HIF), and signaling through protein kinase C. It is postulated that iron chelation, through interruption of these pathways, blocks cell cycle progression from G0/G1 to S phase of the cell cycle. We will also test whether HIF-mediated vascular endothelial growth factor expression has important effects on endothelial growth and function in cultured cells and a porcine vascular injury model. In AIM 2 we will study myocardial dysfunction due to iron overload in mice. Based on the hypothesis that iron overload induces mitochondrial injury from altered redox signaling or release of toxic levels of oxygen free radicals, alterations in specific targets, including cardiolipin, frataxin, manganese superoxide dismutase and heat shock proteins, will be examined. Because of the limitations of currently available iron chelators, we will study whether myocardial injury due to iron overload can be prevented by parenteral or oral administration of exochelin. Exochelin in desferri-form will be administered with or without concomitant use of an L-channel calcium blocker, which prevents myocyte uptake of non-transferrin-bound iron. In Aim 3 we will test the hypothesis that the lipid-solubility of exochelins accounts for their potency as anti-proliferative and cardio-protective agents because of site-specific iron chelation in the lipid portions of the cell membrane. Completion of these studies will greatly enhance our knowledge of the cardiovascular pathophysiology of iron-mediated redox reactions and evaluate the potential usefulness of a unique iron chelator, exochelin, for preventing vascular or myocardial injury through this mechanism.

描述（由申请人提供）：我们提出铁在血管和心肌损伤的重要不良过程中起关键作用。铁介导的氧化还原信号可能调节生长因子和细胞周期进程，导致血管损伤后再狭窄。过量的铁会导致心功能障碍。为了研究这些问题，我们将采用一种新的脂溶性铁螯合剂，它可以快速进入细胞，并且在防止铁介导的反应方面比目前可用的螯合剂更有效。在AIM 1中，我们将在培养的人血管平滑肌和内皮细胞中研究铁介导的氧化还原信号在核因子- κ B、激活蛋白-1和缺氧诱导因子（HIF）的转录激活中的作用，以及通过蛋白激酶c的信号传导。假设铁螯合通过中断这些途径，阻断细胞周期从G0/G1期到S期的进展。我们还将在培养细胞和猪血管损伤模型中测试hif介导的血管内皮生长因子表达是否对内皮生长和功能有重要影响。在AIM 2中，我们将研究铁超载引起的小鼠心肌功能障碍。基于铁超载通过改变氧化还原信号或释放有毒水平的氧自由基诱导线粒体损伤的假设，将检查特定靶点的改变，包括心磷脂、拉他蛋白、锰超氧化物歧化酶和热休克蛋白。由于目前可用的铁螯合剂的局限性，我们将研究是否可以通过肠外或口服外螯素来预防铁过载引起的心肌损伤。地铁素形式的外chelin将与或不同时使用l通道钙阻滞剂，以防止肌细胞摄取非转铁蛋白结合的铁。在Aim 3中，我们将检验外螯合蛋白的脂溶性解释其作为抗增殖和心脏保护剂的效力的假设，因为细胞膜脂质部分的位点特异性铁螯合。这些研究的完成将大大提高我们对铁介导的氧化还原反应的心血管病理生理学的认识，并评估一种独特的铁螯合剂外螯合蛋白通过这种机制预防血管或心肌损伤的潜在用途。