Iron-Mediated Cardiovascular Injury

铁介导的心血管损伤

• 批准号: 7008880
• 负责人: LAWRENCE HORWITZ
• 金额: $ 33.01万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008880
• 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）：我们认为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。过量的铁超载导致心脏功能障碍。为了研究这些问题，我们将采用一种新的脂溶性铁螯合剂，它能迅速进入细胞，在防止铁介导的反应方面比迄今为止可用的螯合剂有效得多。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对核因子-κ B、激活蛋白-1和缺氧诱导因子（HIF）转录激活的作用，以及通过蛋白激酶C的信号传导。据推测，铁螯合，通过中断这些途径，阻断细胞周期从G 0/G1期到S期的细胞周期进程。我们还将测试HIF介导的血管内皮生长因子表达是否对培养细胞和猪血管损伤模型中的内皮生长和功能具有重要影响。在AIM 2中，我们将研究小鼠铁过载引起的心肌功能障碍。基于铁超载诱导线粒体损伤的假设，从改变氧化还原信号或释放有毒水平的氧自由基，改变特定的目标，包括心磷脂，共济失调蛋白，锰超氧化物歧化酶和热休克蛋白，将进行检查。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给药exochelin预防由于铁过载引起的心肌损伤。脱铁形式的外螯铁蛋白将与或不与L-通道钙阻滞剂同时使用，其防止肌细胞摄取非转铁蛋白结合的铁。在目标3中，我们将测试的假设，外螯素的脂溶性占其作为抗增殖和心脏保护剂的效力，因为在细胞膜的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的心血管病理生理学的铁介导的氧化还原反应的知识，并评估潜在的有用性的一个独特的铁螯合剂，exochelin，通过这种机制，防止血管或心肌损伤。

项目成果

An iron-binding exochelin prevents restenosis due to coronary artery balloon injury in a porcine model.

铁结合外螯素可预防猪模型中冠状动脉球囊损伤引起的再狭窄。

• DOI: 10.1161/hc4301.097194
• 发表时间: 2001
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Rosenthal,EA;Bohlmeyer,TJ;Monnet,E;MacPhail,C;Robertson,AD;Horwitz,MA;Burchenal,JE;Horwitz,LD
• 通讯作者: Horwitz,LD

Desferri-Exochelin, a lipid-soluble, hexadentate iron chelator, effectively removes tissue iron.

Desferri-Exochelin 是一种脂溶性六齿铁螯合剂，可有效去除组织铁。

• DOI: 10.1016/j.trsl.2006.03.003
• 发表时间: 2006
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Hodges,YvonneK;Weinberger,HowardD;Stephens,Janet;Horwitz,MarcusA;Horwitz,LawrenceD
• 通讯作者: Horwitz,LawrenceD

Lipophilic siderophores of Mycobacterium tuberculosis prevent cardiac reperfusion injury.

• DOI: 10.1073/pnas.95.9.5263
• 发表时间: 1998-04
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: L. Horwitz;N. A. Sherman;Y. Kong;A. Pike;J. Gobin;P. Fennessey;M. Horwitz

A lipid-soluble iron chelator alters cell cycle regulatory protein binding in breast cancer cells compared to normal breast cells.

与正常乳腺细胞相比，脂溶性铁螯合剂改变乳腺癌细胞中的细胞周期调节蛋白结合。

• 发表时间: 2007
• 期刊: Journal of experimental therapeutics & oncology
• 作者: Pahl,PaulaMB;Reese,SaraM;Horwitz,LawrenceD
• 通讯作者: Horwitz,LawrenceD