Mechanisms Underlying Mitrochondrial Dysfunction in the Diabetic Heart

描述(申请人提供)：线粒体网络，作为氧化应激的来源和受害者，已经成为许多重要疾病的主要起因，其中糖尿病和肥胖患者的心肌病是最相关的之一。我们的长期目标是确定在糖尿病、肥胖和心力衰竭等常见疾病中，线粒体衍生的活性氧(ROS)和氮(RNS)物种的产生所涉及的关键机制步骤。在线粒体作为ROS和RNS发挥重要生理作用的关键信号细胞器这一新兴观点中，我们的目标是更全面和定量地了解线粒体在糖尿病相关代谢、收缩和电功能障碍的(病理)生理学中的作用。目前该方案的主要假设是：1)糖尿病动物的心肌细胞在高血糖时更容易受到氧化/亚硝酸盐应激引起的线粒体功能障碍的影响；2)糖尿病心脏由于其代谢状态的损害，更容易发生传导障碍、心律失常和收缩功能障碍。我们的假设基于以下观察：1)一旦达到ROS的阈值水平，心肌细胞的线粒体网络对环境扰动极其敏感，导致整个细胞的线粒体膜电位(？M)崩溃和心肌细胞的不兴奋；2)ROS和RNS的生物利用度是通过共同的机制调节的；3)外源性或内源性ROS清除剂或一氧化氮产生抑制剂可以很容易地阻止？M的振荡；4)线粒体能量的振荡驱动表面KATP电流和动作电位的振荡，影响完整心脏缺血后心律失常和收缩功能障碍的发生率。与公共健康相关：糖尿病是由胰岛素分泌或作用不足引起的，影响全球1.5亿人和近6%的美国人口。世界卫生组织最近的一项研究估计，到2030年，这一数字将增长到3.66亿。实现本研究的目标将有助于更好地了解线粒体功能障碍如何影响糖尿病患者心脏并发症的发生率和严重程度，并将确定针对这一常见疾病的治疗策略的新靶点。

DESCRIPTION (provided by applicant): The mitochondrial network, as a source and victim of oxidative stress has become a dominant player at the origin of many important diseases, among which cardiomyopathy in diabetic and obese patients ranks as one of the most relevant. Our long-term goal is to identify the critical mechanistic steps involved in the production of mitochondrially-derived reactive oxygen (ROS) and nitrogen (RNS) species in common diseases, such as diabetes, obesity, and heart failure. In the emerging view of the mitochondrion as a key signaling organelle in which ROS and RNS fulfill critical physiological roles, we aim to achieve a more comprehensive and quantitative understanding of its role in the (patho)physiology of diabetes related metabolic, contractile, and electrical dysfunction. The main hypotheses of the current proposal are that: 1) Cardiac myocytes from diabetic animals are more susceptible to mitochondrial dysfunction caused by oxidative/nitrosative stress in response to hyperglycemia, and 2) the diabetic heart is more susceptible to the incidence of conduction disturbances, arrhythmias and contractile dysfunction because of its compromised metabolic status. We base our hypotheses on the following observations: 1) the mitochondrial network of a cardiomyocyte is extremely sensitive to environmental perturbations once a threshold level of ROS is attained, leading to a cell-wide collapse of the mitochondrial membrane potential (??m) and myocyte inexcitability; 2) ROS and RNS bioavailability are regulated through common mechanisms; 3) oscillations of ??m can be readily prevented by exogenous or endogenous ROS scavengers, or nitric oxide production inhibitors; 4) oscillations of mitochondrial energetics drive oscillations of surface KATP current and action potentials, affecting the incidence of post-ischemic arrhythmias and contractile dysfunction in the intact heart. PUBLIC HEALTH RELEVANCE: Diabetes is caused by a deficiency in the secretion or action of insulin, affecting >150 million individuals worldwide and nearly 6% of the US population. A recent study by the World Health Organization estimates that those numbers will grow to 366 million by 2030. Achieving the aims of the present study will lead to a better understanding of how mitochondrial dysfunction affects the incidence and severity of cardiac complications among diabetics, and will identify novel targets for therapeutic strategies against this common disease.