IRON MEDIATED CARDIOVASCULAR INJURY

铁介导的心血管损伤

• 批准号: 6351492
• 负责人: LAWRENCE HORWITZ
• 金额: $ 26.92万
• 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 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6351492
• 关键词: apoptosis; cardiac myocytes; cardiovascular disorder chemotherapy; cell cycle; cell growth regulation; cell proliferation; chelating agents; chelation therapy; chemoprevention; cyclin dependent kinase; deferoxamine; dogs; drug design /synthesis /production; free radical oxygen; human tissue; iron metabolism; myocardial infarct sizing; myocardial ischemia /hypoxia; nonhuman therapy evaluation; oxidative stress; reperfusion; swine; tissue /cell culture; vascular smooth muscle; western blottings

Iron plays a critical role in two processes of great importance in cardiovascular diseases: vascular smooth muscle proliferation and reperfusion injury. We have isolated, synthesized and completed highly promising pilot studies on a family of iron chelators,exochelins secreted by Mycobacterium tuberculosis. They block redox reactions and are unique among chelators in that they are lipid soluble, a property that permits them to rapidly enter cells and be physiologically active at extremely low concentrations. In the desferri-form, exochelins prevent damage by reactive oxygen species to cultured cardiac myocytes, reperfusion injury in isolated rabbit hearts and proliferation of cultured human vascular smooth muscle cells (VSMCs). We propose to elucidate the molecular mechanisms by which iron chelation with lipid-soluble exochelins prevent VSMC growth. In cultured human VSMCs we will test the hypothesis that exochelins block progression through the cell cycle at both the G1 and S phases by inhibiting activity of cyclin-dependent kinases. We propose that this occurs through upregulation of inhibitory proteins, particularly p21. We will examine the uptake and intracellular distribution of exochelins and the extent to which they influence VSMC growth through interruption of redox signaling. In separate studies we will assess whether exochelins given intramurally or intracoronary will prevent coronary artery restenosis due to VSMC proliferation following angioplasty in a porcine model. We will also assess the effects of desferri-exochelins given during reperfusion on myocardial infarct size, normalized for volume at risk and collateral blood flow, in a rigorous canine model involving 90 min of coronary occlusion and 48 hours of reperfusion. Finally we will examine whether desferri-exochelins prevent apoptosis, a genetically programmed mechanism of cell death that has been associated with reperfusion injury. We believe that exochelins have extraordinary potential for prevention of vascular and reperfusion injury, and are uniquely suitable for understanding the role of iron in these processes. This project would offer important mechanistic information at the molecular level and critical potential proof of principle for important therapeutic applications. We submit that our considerable progress to date and our unique familiarity with exochelins establishes that we have the capabilities to complete these exciting studies.

铁在两个非常重要的过程中起着关键作用 心血管疾病：血管平滑肌增殖 和再灌流损伤。我们已经分离、合成和 完成了对一个铁族的非常有希望的初步研究 螯合剂，结核分枝杆菌分泌的胞外蛋白。 它们阻止氧化还原反应，在螯合剂中是独一无二的 它们是脂溶的，这一特性使它们能够迅速 进入细胞并在极低的条件下保持生理活性 浓度。在去铁体中，外周血球蛋白可防止损伤 通过培养的心肌细胞中的活性氧， 兔离体心再灌流损伤与心肌细胞增殖 培养的人血管平滑肌细胞(VSMCs)。我们建议 阐明铁螯合作用的分子机制 具有脂溶性的胞外蛋白可防止VSMC的生长。在培养中 我们将检验外周血凝素阻断血管平滑肌细胞的假说 细胞周期在G1期和S期的进展 抑制细胞周期蛋白依赖性激酶的活性。我们建议 这是通过上调抑制蛋白来实现的， 尤其是p21。我们将检查摄取和细胞内 胞外蛋白的分布及其影响程度 VSMC通过阻断氧化还原信号而生长。在单独的 我们将评估外周血凝素是经皮内给药还是 冠状动脉内将预防VSMC导致的冠状动脉再狭窄 猪血管成形术后的增殖。我们会 同时评估去铁蛋白在治疗中的作用 心肌梗死面积的再灌流，归一化的体积在 在严格的犬类模型中，风险和侧支血流 涉及冠状动脉闭塞90分钟和48小时 再灌流。最后，我们将检查去铁蛋白是否 防止细胞凋亡，这是细胞的一种遗传编程机制 与再灌注损伤相关的死亡。我们 相信外周血球蛋白具有非凡的潜力 防止血管和再灌注损伤，是独一无二的 适合于理解铁在这些过程中的作用。 该项目将提供重要的机械信息在 分子水平和临界势能的原理证明 重要的治疗应用。我们提交我们的 到目前为止取得了相当大的进展，我们对 外周血凝素证实我们有能力完成 这些令人兴奋的研究。