Mitochondrial Protection Within Chronically Ischemic Myocardium

慢性缺血心肌内的线粒体保护

• 批准号: 7578495
• 负责人: EDWARD O. MCFALLS
• 金额: $ 35.35万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578495
• 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）：尽管血液流量较长，但心肌组织仍可以保持生存。该实体被称为“休眠”，对实验观察到，对晚期冠状动脉疾病和缺血性心肌病的患者具有重要的临床意义。在此提案中，我们将检验以下假设：在“第二个保护窗口”（SWOP）中，在线粒体内部的无偶联蛋白（UCP）-2的表达是线粒体内的适应性过程，它是防止缺氧的。在AIM＃1中，我们假设UCP-2通过减少超氧化物的产生并防止导致线粒体通透性过渡孔的形成和细胞色素C损失来保护线粒体免受缺氧 - 耐氧化。我们的初步数据表明UCP-2与保护之间存在重要的关系，因为GDP停用了UCP-2并抑制了压力抗性。作为AIM＃2的一部分，我们将通过在基础条件下评估小鼠心脏中的线粒体保护程度，并在过氧化物酶体增殖物激活受体（PPAR）γ刺激下，并使用慢性饮食饮食中的甲虫刺激。我们在此重新提交中的初步数据表明，野生型心脏的UCP-2有效增加，但与Pioglitazone的ucp-2 KO小鼠没有增加，以及从小鼠心脏中隔离的线粒体保护的保护增加。我们的中心问题是，针对重复供应需求的线粒体适应可能会抵消冬眠心脏的保护性线粒体适应性，但导致高工作状态下的次最大能量和功能反应。因此，在AIM＃3中，我们将测试高剂量多丁胺和UCP-2的离体表达期间体内透壁能量与功能之间的关系。我们来自冬眠猪心脏的初步数据表明，多丁胺期间磷酸化状态（PCR）与ATP比例测量的磷酸化状态与Vivo的UCP-2含量增加相称。为了建立更直接的关系，我们将测试与吡格列酮对PPAR-GAMMA的慢性刺激是否会进一步增加UCP-2的线粒体表达，从而导致跨膜能量和功能的增加。最后，作为AIM＃4的一部分，我们将使用ITRAC测试线粒体ATP合酶是否可能导致冬眠组织中观察到的基础区域血流减少的潜在因素，以响应猪模型中的慢性吡格列酮而进一步降低。潜在对卫生护理 - 线粒体的影响是严重氧化剂损害的主要来源。它们有可能成为CHF患者的重要治疗靶点。我们提出的研究解决了线粒体保护的机制，这可能导致新的治疗方法。我们还将检查葡萄球菌的影响，糖尿病的疗法及其在UCP-2诱导中的潜在作用对CHF的进化。公共卫生相关性：冠状动脉疾病的渐进性心力衰竭是最常见的死亡原因。血运重建疗法和抗心痛的装置可预防猝死，但是在大多数接受这些治疗的患者中，细胞死亡的进行性逐渐导致令人衰弱的疾病仍然是流行病比例的疾病。该提案将解决线粒体适应以防止凋亡或细胞死亡的潜在机制，以防止血流急性减少，但长期以最大的能量产生。我们将专注于心力衰竭的猪模型，该模型与血液流动到心脏可行区域的减少有关。该提案将测试通过最先进的MRI成像衡量的线粒体生产是否会在功能的持续降低中发挥作用。使用此模型，我们提出，与心力衰竭相关的糖尿病患者中使用的一类药物以类似的方式改变了线粒体能量的产生。