Mitochondrial Protection Within Chronically Ischemic Myocardium

慢性缺血心肌内的线粒体保护

• 批准号: 7851337
• 负责人: EDWARD O. MCFALLS
• 金额: $ 36.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851337
• 关键词: Acute; Address; Anoxia; Apoptosis; Area; Arts; Blood flow; Cardiomyopathies; Cause of Death; Cell Death; Cell Death Process; Chronic; Clinical; Coronary Arteriosclerosis; Coupling; Data; Devices; Disease; Dobutamine; Dose; Drug usage; Epidemic; Evolution; Family suidae; Generations; Healthcare; Heart; Heart failure; Hibernation; Image; Ischemia; Lead; Magnetic Resonance Imaging; Measures; Mitochondria; Mitochondrial Proton-Translocating ATPases; Modeling; Mus; Myocardial Ischemia; Myocardial tissue; Myocardium; Oxidants; PPAR gamma; Pathway interactions; Patients; Phosphocreatine; Phosphorylation; Pioglitazone; Play; Process; Production; Proton-Translocating ATPases; Regional Blood Flow; Research; Resistance; Respiration; Role; Source; Stress; Sudden Death; Superoxides; Tachycardia; Testing; Thiazolidinediones; Tissues; Transgenic Mice; UCP2 protein; Wild Type Mouse; Work; cytochrome c; diabetes mellitus therapy; diabetic patient; in vivo; indexing; mitochondrial permeability transition pore; novel; preconditioning; prevent; public health relevance; respiratory; response; therapeutic target

DESCRIPTION (provided by applicant): Myocardial tissue can remain viable, despite a prolonged period of reduced blood flow. Referred to as "hibernation", the entity is observed experimentally and has important clinical implications for patients with advanced coronary artery disease and ischemic cardiomyopathy. In this proposal, we will test the hypothesis that expression of uncoupling protein (UCP)-2, as an adaptive process within mitochondria from hibernating and preconditioned heart tissue in the "Second Window of Protection" (SWOP), is protective against anoxia. In AIM #1, we hypothesize that UCP-2 protects mitochondria against anoxia-reoxygenation, by reducing superoxide generation and preventing a pathway that leads to mitochondrial permeability transition pore formation and cytochrome c loss. Our preliminary data suggest an important relationship between UCP-2 and protection, because GDP deactivates UCP-2 and inhibits stress-resistance. As part of AIM #2, we will further develop the concept by assessing the degree of mitochondrial protection in mouse hearts under basal conditions and following peroxisome proliferator activated receptor (PPAR) gamma stimulation with chronic dietary administration of pioglitazone. Our preliminary data in this resubmission show a robust increase in UCP-2 from hearts of wild type but not UCP-2 KO mice with pioglitazone, along with an increase in protection from the isolated mitochondria from the mouse hearts. Our central question is that mitochondrial adaptations against repetitive supply-demand ischemia might offset oxidant damage as a protective mitochondrial adaptation in hibernating hearts, but result in a submaximal energetic and functional response at high work states. Therefore, in AIM #3, we will test the relationship between in vivo transmural energy and function during high dose dobutamine and ex vivo expression of UCP-2. Our preliminary data from hibernating pig hearts show that the phosphorylation state, as measured by the phosphocreatine (PCr) to ATP ratio during dobutamine is reduced proportionate to the increased UCP-2 content ex vivo. To establish a more direct relationship, we will then test whether chronic stimulation of PPAR-gamma with pioglitazone will further increase the mitochondrial expression of UCP-2, leading to an additional decrement in transmural energy and function. Finally, as part of AIM #4, we will use iTRAC, to test whether mitochondrial ATP synthase, a potentially contributing factor to the observed reductions in basal regional blood flow in hibernating tissue, will be further reduced in response to chronic pioglitazone in the pig model. Potential Impact on Health Care- Mitochondria are a major source of severe oxidant damage. They have the potential for being an important therapeutic target for patients with CHF. We propose studies that address mechanisms of mitochondrial protection that may lead to novel treatments. We will also examine the effects of glitazones, a therapy for diabetes, and its potential role in UCP-2 induction on the evolution of CHF. PUBLIC HEALTH RELEVANCE: Progressive heart failure from coronary artery disease is the most common cause of death. Revascularization therapies and anti-tachycardia devices are available to prevent sudden death, but among the majority of patients who have received these treatments, the progressive process of cell death that leads to a debilitating disease remains of epidemic proportion. This proposal will address potential mechanisms by which mitochondria adapt to prevent apoptosis or cell death against acute reductions in blood flow, but limit maximal energy production chronically. We will focus on a pig model of heart failure that is associated with a reduction in blood flow to a viable area of the heart. The proposal will test whether the mitochondrial production of energy, as measured by state-of-the-art MRI imaging, will play a role in the sustained reductions in function. Using this model, we propose that a class of drugs used in diabetic patients that has been associated with heart failure exacerbations, alters the mitochondrial energy production in a similar way.

描述（由申请人提供）：心肌组织可以保持活力，尽管长时间血流量减少。该实体被称为“冬眠”，是实验观察到的，对晚期冠状动脉疾病和缺血性心肌病患者具有重要的临床意义。在本提案中，我们将验证解偶联蛋白(UCP)-2的表达作为线粒体内冬眠和预处理心脏组织在“第二保护窗口”（SWOP）中的适应性过程，对缺氧具有保护作用的假设。在AIM #1中，我们假设UCP-2通过减少超氧化物的产生和阻止导致线粒体通透性、过渡孔形成和细胞色素c损失的途径来保护线粒体免受缺氧再氧化。我们的初步数据表明，UCP-2与保护之间存在重要关系，因为GDP使UCP-2失活，抑制了抗逆性。作为AIM #2的一部分，我们将进一步发展这一概念，通过评估基础条件下小鼠心脏的线粒体保护程度，并通过长期饮食给药吡格列酮刺激过氧化物酶体增殖物激活受体(PPAR) γ。我们在这次重新提交的初步数据显示，使用吡格列酮的野生型小鼠心脏中UCP-2的显著增加，而UCP-2的KO小鼠心脏中UCP-2的增加，以及小鼠心脏中分离线粒体的保护增加。我们的核心问题是，线粒体对重复供需缺血的适应可能会抵消氧化损伤，作为冬眠心脏中的保护性线粒体适应，但在高工作状态下会导致次极大的能量和功能反应。因此，在AIM #3中，我们将测试高剂量多巴酚丁胺时体内跨壁能量和功能与体外UCP-2表达之间的关系。我们从冬眠猪心脏中获得的初步数据表明，多巴酚丁胺作用下，磷酸化状态（通过磷酸肌酸（PCr）与ATP的比值测量）与体外UCP-2含量的增加成比例地降低。为了建立更直接的关系，我们将测试吡格列酮对ppar - γ的慢性刺激是否会进一步增加UCP-2的线粒体表达，从而导致跨壁能量和功能的额外下降。最后，作为AIM #4的一部分，我们将使用iTRAC来测试线粒体ATP合酶是否会在猪模型中进一步减少，ATP合酶是观察到的冬眠组织中基础区域血流量减少的潜在因素。对医疗保健的潜在影响——线粒体是严重氧化损伤的主要来源。它们有可能成为慢性心力衰竭患者的重要治疗靶点。我们提出的研究，解决线粒体保护的机制，可能导致新的治疗。我们还将研究格列酮（一种治疗糖尿病的药物）的作用及其在UCP-2诱导中对CHF演变的潜在作用。公共卫生相关性：冠状动脉疾病引起的进行性心力衰竭是最常见的死亡原因。血管重建治疗和抗心动过速装置可用于预防猝死，但在接受这些治疗的大多数患者中，细胞死亡的进行性过程导致衰弱性疾病仍然是流行病。这一建议将解决线粒体适应防止细胞凋亡或细胞死亡的潜在机制，以防止急性血流量减少，但长期限制最大能量的产生。我们将集中在猪心力衰竭模型，这是与血液流向心脏的可行区域减少有关。这项提议将测试由最先进的核磁共振成像测量的线粒体产生的能量是否会在功能的持续下降中发挥作用。利用这个模型，我们提出一类用于糖尿病患者的药物，与心力衰竭加重有关，以类似的方式改变线粒体能量的产生。

项目成果

Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization.

尽管在血运重建后 4 周成功进行了冠状动脉旁路移植术，但冬眠心肌内解偶联蛋白 2 的表达仍然增加。

• DOI: 10.1016/j.jss.2014.08.003
• 发表时间: 2015
• 期刊: The Journal of surgical research
• 作者: Holley,ChristopherT;Duffy,CaylaM;Butterick,TammyA;Long,EricK;Lindsey,MeganE;Cabrera,JesúsA;Ward,HerbertB;McFalls,EdwardO;Kelly,RosemaryF
• 通讯作者: Kelly,RosemaryF