Mitochondria-mediated mechanisms of ferroptosis in response to cardiac ischemia-reperfusion injury

线粒体介导的铁死亡响应心脏缺血再灌注损伤的机制

• 批准号: 10681495
• 负责人: Sabzali Javadov
• 金额: $ 15万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681495
• 关键词: Accounting; Apoptosis; Autophagocytosis; Biology; Cardiac; Cardiac Myocytes; Cell Death; Cells; Cessation of life; Citric Acid Cycle; Complex; Coronary heart disease; Cysteine; Cystine; Data; Dependence; Development; Endoplasmic Reticulum; Exposure to; Gases; Generations; Glutamates; Heart; Image; Imaging Techniques; Ions; Iron; Ischemia; Lipoxygenase; Maps; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial dysfunction; Myocardium; Necrosis; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathogenesis; Phosphatidylethanolamine; Phospholipids; Play; Polyunsaturated Fatty Acids; Prevention; Process; Production; Reduced Glutathione; Reducing Agents; Reperfusion Injury; Reperfusion Therapy; Resolution; Role; Severities; Severity of illness; Signal Transduction; Spectrometry, Mass, Secondary Ion; System; Techniques; Therapeutic; Therapeutic Intervention; antiporter; cardioprotection; comparative; coronary perfusion; dihydrolipoic acid; effectiveness evaluation; glutathione peroxidase; heart damage; in vivo; inhibitor; innovation; ischemic injury; mass spectrometric imaging; mortality; novel; novel therapeutic intervention; oxidation; prevent; response; restoration; selenoprotein; specific biomarkers; therapeutically effective; treatment strategy

ABSTRACT Coronary heart disease is the leading cause of mortality and morbidity worldwide that occurs due to the detrimental effects of myocardial infarction (MI)/ischemia-reperfusion injury (IRI). Mechanisms of MI/IRI are not completely clear, and hence, there are no effective therapeutic strategies; current therapeutic approaches to mitigate heart damage mostly focus on restoring coronary perfusion but not limiting reperfusion injury. Multiple forms of cell death occur at different stages of post-MI/IRI depending on the severity of the disease. This project will elucidate the regulatory mechanisms of a recently discovered iron- dependent programmed cell death, ferroptosis, in cardiac IRI. Ferroptosis arises via excessive oxygenation of phospholipids (PLs) accompanied by the insufficient capacity of a selenoprotein glutathione peroxidase 4 (GPX4) to eliminate oxidized PLs, particularly, phosphatidylethanolamine (PEox) at the expense of reduced glutathione (GSH). We have recently identified and quantified pro-ferroptotic PEox species in response to RSL3 (GPX4 inhibitor, ferroptosis inducer) in cardiomyocytes by a state-of-art technique. In addition, our preliminary studies revealed accumulation of ferroptotic PEox species in mitochondria isolated from hearts exposed to global IRI as well as from cardiomyocytes challenged with RSL3. We propose that mitochondria participate in MI/IRI-induced ferroptotic signaling through two major GSH- dependent mechanisms: i) IR-induced mitochondrial ROS generation by ETC and TCA cycle deplete GSH, and hence, inactivate the GSH/GPX4 system, and ii) glutamate deficiency due to inhibition of glutaminolysis in mitochondria inhibits GSH synthesis as a result of low glutamate and cysteine levels. Thus, this project will explore a novel paradigm by investigating the role of mitochondria in cardiac IRI ferroptosis. Our central hypothesis is that mitochondria are engaged in ferroptosis induced by cardiac IRI through diminishing GPX4 activity and inability to control the accumulation of pro-ferroptotic PEox species. Also, we propose that major cell death mechanisms have different impacts during post-MI/IRI depending on the severity and duration of post-MI/IRI. Hence, we will evaluate specific biomarkers to distinguish the contributions of apoptosis, ferroptosis, necroptosis, and pyroptosis to post-MI/IRI. Two approaches will be employed to mitigate cardiac IRI via i) specific suppression of mtROS production/GSH depletion, and ii) replenishment of the GSH pool by a potent reductant lipoic/dihydrolipoic acid (LA/DHLA). Specific Aims of the project will (i) determine comparative contributions of ferroptosis to cardiac dysfunction during IRI, (ii) explore molecular mechanisms of mitochondria-mediated ferroptotic signaling in cardiac cells, and (iii) examine the effectiveness of novel inhibitors of ferroptosis against cardiac IRI. The project will establish the contribution of ferroptosis, in comparison with other major cell death mechanisms, to MI/IRI-induced cardiac dysfunction, and discover new mitochondria-mediated mechanisms of ferroptotic signaling that will lead to innovative therapeutic strategies for the treatment of cardiac IRI.

抽象的 冠心病是全球死亡率和发病率的主要原因，这是由于 心肌梗死（MI）/缺血再灌注损伤（IRI）的有害作用。 MI/IRI的机制 并不完全清楚，因此，没有有效的治疗策略。当前的治疗性 减轻心脏损伤的方法主要集中于恢复冠状动脉灌注，但不限制 再灌注损伤。多种形式的细胞死亡发生在MI/IRI的不同阶段，具体取决于 疾病的严重程度。该项目将阐明最近发现的铁的调节机制 心脏IRI中依赖的程序性细胞死亡，铁毒性。铁凋亡是通过过量的氧合而产生的 磷脂（PLS）伴随着硒蛋白谷胱甘肽过氧化物酶的能力不足 4（GPX4）消除了氧化的PL，特别是磷脂酰乙醇胺（PEOX），以牺牲 减少谷胱甘肽（GSH）。我们最近在 通过最先进的技术对心肌细胞中RSL3（GPX4抑制剂，铁吞作用诱导剂）的反应。在 此外，我们的初步研究表明，线粒体中的血毒性peox物种的积累 从暴露于全球IRI的心脏以及RSL3挑战的心肌细胞中分离出来。我们 提出线粒体通过两个主要的GSH- 依赖机制：I）IR诱导的线粒体ROS通过ETC和TCA循环耗尽GSH， 因此，由于抑制了GSH/GPX4系统，II）谷氨酸缺乏症 线粒体中的谷氨酰胺分解抑制了谷氨酸和半胱氨酸水平低的结果。 因此，该项目将通过研究线粒体在心脏IRI中的作用来探索一种新的范式 铁凋亡。我们的中心假设是线粒体从事心脏IRI诱导的血吞作用 通过减少GPX4活性并无法控制促侵蚀性peox物种的积累。 此外，我们建议在MI/IRI期间，主要的细胞死亡机制具有不同的影响 关于MI/IRI后的严重性和持续时间。因此，我们将评估特定的生物标志物以区分 细胞凋亡，铁凋亡，坏死和凋亡对MI/IRI后的贡献。两种方法将是 通过i）用于减轻心脏IRI的使用i）特异性抑制MTROS生产/GSH耗竭，ii） 通过有效的还原剂lipoic/二氢丙酸（LA/DHLA）补充GSH池。具体目标 该项目将（i）确定在IRI期间铁凋亡对心脏功能障碍的比较贡献，（ii） 探索心脏细胞中线粒体介导的甲状腺毒信号传导的分子机制，（iii） 检查新型铁凋亡对心脏IRI的有效性。该项目将建立 与其他主要细胞死亡机制相比，铁铁作用的贡献对Mi/Iri诱导 心脏功能障碍，并发现将新的线粒体介导的螺旋性信号的机制 导致用于治疗心脏IRI的创新治疗策略。