NO/STEM CELLS IN THE DIABETIC HEART

糖尿病心脏中的无细胞/干细胞

• 批准号: 7211369
• 负责人: Thomas H HINTZE
• 金额: $ 41.14万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211369
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alloxan; Animals; Anterior; Area; Automobile Driving; Biological Availability; Blood Vessels; Blood flow; Body Weight; Canis familiaris; Cardiac; Cell Differentiation process; Cells; Conscious; Contracts; Coronary; Coronary artery; Data; Diabetes Mellitus; Epidemic; Evolution; Fatty Acids; Forskolin; Functional disorder; Funding; Genetic Transcription; Glucose; Grant; Growth Factor; Heart; Heart Diseases; Hepatocyte Growth Factor; Homing; In Vitro; Incidence; Indigenous; Infarction; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Ischemia; Keto Acids; Lead; Messenger RNA; Metabolic; Metabolism; Methods; Molecular Probes; Myocardial; Myocardial Ischemia; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Oxygen; Oxygen Consumption; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Plasma; Population; Premature Mortality; Process; Production; Proteins; Radioactive; Rate; Rattus; Recruitment Activity; Reflex action; Regulation; Relative (related person); Research Personnel; Role; Signal Transduction; Simvastatin; Somatomedins; Sorting - Cell Movement; Stem cells; Streptozocin; Superoxides; Time; Translations; Up-Regulation; Vascular Diseases; Water; Week; Work; Zucker Rats; day; design; diabetic; diabetic rat; falls; glucose uptake; in vivo; preference; programs; response; size; therapy design; uptake

DESCRIPTION (provided by applicant): Diabetes is associated with both coronary vascular disease and cardiac ischemia resulting in accelerated and aggressive cardiac disease. In the previous 3 years we have focused on the potential role of reduced NO production on the diabetic heart. We have found that alloxane induced type I diabetes is characterized by increased mRNA for eNOS but reduced protein and NO production. We have also shown that there are marked shifts in cardiac substrate use, consistent with the role of NO in the control of cardiac fatty acid and glucose uptake. We have also found that the decrease in NO production results in altered regulation of myocardial oxygen consumption by NO perhaps contributing to a mismatch between oxygen delivery and demand. In the current application we will continue to focus on the role of NO in the control of cardiac function and metabolism. In specific aim 1, we will examine the potential that phosphorylation can increase the activity of eNOS and compensate for the reduction in eNOS protein which we observed in the diabetic heart. In vitro studies will be used to sort out the signaling mechanism and the Bezold-Jarisch reflex coronary dilation will be used as method to study this in vivo. Previously we have found that diabetes shifts substrate uptake in the heart from fatty acids to keto acids with no glucose uptake despite the marked increase in plasma glucose. We have also found that these shifts occur at about the time that NO production by the heart falls. We will investigate the relationship between NO production and substrate use in the diabetic heart in specific aim 2 of this proposal. Whereas most of our studies have focused on type 1 diabetes, the incidence of type II diabetes is increasing in the population at epidemic rates. To investigate the role of altered NO production and the mechanism responsible we have begun studies in the Zucker fatty rat (Type II) and to contrast those findings with rats treated with Streptozotocin (Type I) or alloxan. Interestingly, and the focus of specific aim 3 we have found that eNOS protein is normal in the heart of the Zucker rat accompanied by a reduction in NO bioactivity (unlike the Strep treated rat where eNOS protein is reduced by 50%). These data imply an important role for superoxide anion in Type II diabetes and will be the focus of this specific aim. In specific aim 4 we will determine whether treatment of the diabetic dog heart with growth factors to recruit cardiac stem cells results in alterations in cardiac function after infarction. Because diabetes is characterized by aggressive myocardial ischemia we postulate that in the diabetic heart compensatory mechanisms such as stem cell recruitment are deficient resulting in exaggerated ischemia. Thus this proposal will continue work on the role of NO in the control of cardiac function and metabolism and extend these studies to the role of cardiac stem cells in the genesis and treatment of the diabetic ischemic heart.

描述(申请人提供)：糖尿病与冠状动脉血管疾病和心脏缺血有关，导致加速和侵袭性心脏病。在过去的3年里，我们一直专注于减少NO产生对糖尿病心脏的潜在作用。我们发现，四氧嘧啶诱导的I型糖尿病的特点是eNOS的mRNA表达增加，但蛋白质和NO的产生减少。我们还表明，心脏底物的使用发生了显著的变化，这与NO在控制心脏脂肪酸和葡萄糖摄取中的作用是一致的。我们还发现，NO生成量的减少导致了心肌耗氧调节的改变，这可能是导致氧供需不匹配的原因之一。在目前的应用中，我们将继续关注NO在心脏功能和代谢调控中的作用。在特定的目标1中，我们将检测磷酸化可以增加eNOS活性并补偿我们在糖尿病心脏中观察到的eNOS蛋白减少的可能性。体外研究将用于梳理信号机制，Bezold-Jarisch反射性冠状动脉扩张将作为体内研究方法。此前，我们已经发现，尽管血糖显著升高，但糖尿病会将心脏对底物的摄取从脂肪酸转变为酮酸，而不摄取葡萄糖。我们还发现，这些转变大约发生在心脏没有产量下降的时候。在本提案的特定目标2中，我们将研究糖尿病心脏中一氧化氮的产生和底物使用之间的关系。虽然我们的大多数研究都集中在1型糖尿病上，但II型糖尿病在人群中的发病率正在以流行病的速度增加。为了研究NO产生改变的作用和机制，我们已经开始在Zucker肥胖大鼠(II型)上进行研究，并将这些发现与链脲佐菌素(I型)或四氧嘧啶治疗的大鼠进行比较。有趣的是，也是特定目标3的焦点，我们发现eNOS蛋白在Zucker大鼠的心脏中是正常的，并伴随着NO生物活性的减少(不像Strep处理的大鼠，eNOS蛋白减少了50%)。这些数据暗示了超氧阴离子在II型糖尿病中的重要作用，并将成为这一特定目标的重点。在特定的目标4中，我们将确定用生长因子招募心脏干细胞治疗糖尿病犬心脏是否会导致梗死后心功能的改变。由于糖尿病以侵袭性心肌缺血为特征，我们推测在糖尿病心脏中，干细胞募集等代偿机制不足，导致过度缺血。因此，这项建议将继续研究NO在心脏功能和代谢控制中的作用，并将这些研究扩展到心脏干细胞在糖尿病缺血性心脏的发生和治疗中的作用。