NO/STEM CELLS IN THE DIABETIC HEART

糖尿病心脏中的无细胞/干细胞

• 批准号: 7023880
• 负责人: Thomas H HINTZE
• 金额: $ 41.13万
• 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/7023880
• 关键词: anions; biological signal transduction; cardiovascular disorder therapy; coronary disorder; diabetic cardiomyopathy; dogs; enzyme activity; heart function; heart metabolism; hematopoietic growth factor; hematopoietic stem cells; immunocytochemistry; insulin dependent diabetes mellitus; laboratory rat; myocardial ischemia /hypoxia; nitric oxide; nitric oxide synthase; noninsulin dependent diabetes mellitus; phosphorylation; protein metabolism; superoxides; vasodilation; western blottings

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（由申请人提供）：糖尿病与冠状动脉血管疾病和心脏缺血有关，导致加速和侵略性心脏病。在过去的三年中，我们专注于降低糖尿病心脏的无生产的潜在作用。我们发现Alloxane诱导的I型糖尿病的特征是eNOS的mRNA增加，但蛋白质降低，没有产生。我们还表明，心脏底物的使用有明显的变化，这与NO在控制心脏脂肪酸和葡萄糖摄取中的作用一致。我们还发现，无生产的减少导致心肌氧的调节改变，这也许没有导致氧和需求之间的不匹配。在当前的应用中，我们将继续关注NO在控制心脏功能和代谢中的作用。在特定的目标1中，我们将研究磷酸化可以增加eNOS活性并补偿我们在糖尿病心脏中观察到的eNOS蛋白的降低的潜力。体外研究将用于整理信号传导机制，贝佐尔·贾里什（Bezold-Jarisch）反射冠状动脉膨胀将用作研究该体内研究的方法。以前，我们发现糖尿病将心脏中的底物摄取从脂肪酸转移到酮酸，尽管血浆葡萄糖明显增加，但糖尿病没有葡萄糖吸收。我们还发现，这些转变发生在大约没有心脏产生的时候。我们将在本提案的特定目的2中调查糖尿病心脏中没有生产和底物使用之间的关系。尽管我们的大多数研究都集中在1型糖尿病上，但II型糖尿病的发病率正在以流行病的流行率增加。为了研究改变无生产的作用和负责机制的作用，我们已经开始研究Zucker Fatty Rat（II型），并将这些发现与用链霉菌素（I型）或Alloxan处理的大鼠进行对比。有趣的是，我们发现特定目标3的重点是，eNOS蛋白在扎克大鼠的心脏中是正常的，伴随着无生物活性的降低（与经链球菌处理的大鼠不同，在该大鼠中，eNOS蛋白降低了50％）。这些数据意味着超氧化物阴离子在II型糖尿病中的重要作用，这将是该特定目的的重点。在特定的目标4中，我们将确定是否将糖尿病狗心脏与生长因子募集心脏干细胞的生长因子是否会导致梗塞后心脏功能的改变。由于糖尿病的特征是侵袭性心肌缺血，因此我们假设在糖尿病心脏补偿机制（例如干细胞募集）中会导致缺乏量夸张。因此，该建议将继续致力于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性缺血性心脏的起源和治疗中的作用。