Role of Angiogenesis and Endothelial Progenitor Cells in Diabetic Heart Failure

描述(申请人提供)：在没有冠状动脉疾病(CAD)的情况下，糖尿病会导致心肌功能障碍。这种情况，即糖尿病心肌病(DCM)，被认为是导致糖尿病患者充血性心力衰竭和死亡率增加的原因之一。更严重的是长期糖尿病患者心肌梗死后发生心力衰竭，因为糖尿病在心梗后引起不利的心脏重构，导致更严重的心力衰竭。糖尿病合并或不合并冠心病的心力衰竭(统称为糖尿病心力衰竭)对公众健康构成重大威胁，因为糖尿病的发病率上升，医疗管理延长了糖尿病患者的生命。尽管糖尿病心衰具有这些独特的特点，而且由于糖尿病心衰预后不佳而可能带来的公共健康灾难，但针对糖尿病心脏疾病的主要病理生理问题，目前还没有特效的治疗方法。我们最近发现，血管生成障碍(从已存在的成熟内皮细胞形成新的血管)和循环内皮祖细胞(EPC)的可获得性降低在DCM的发展中起主要作用。最近发现的成人骨髓来源的内皮祖细胞有助于血管的新生发育(血管生成)，通过血管生成和血管生成过程诱导新的血管形成，提高了利用这些细胞修复缺血/梗死心肌的可能性。该项目的长期目标是明确血管系统及其相关生物因素在糖尿病心衰发生发展中的作用，并建立更有效的治疗策略来治疗糖尿病心衰。因此，在这个方案中，我们设计了一系列实验来研究血管生成和血管生成在糖尿病心衰发展中的作用以及EPC移植对糖尿病心衰的影响。在具体目标1中，我们将探讨心肌血管生成缺陷和内皮祖细胞在糖尿病心衰发生发展中的作用。在具体目标2中，我们将通过建立DCM和DM ML模型来探讨EPC移植对糖尿病心衰的治疗作用。在特定的目标3中，我们将探讨介导EPC移植治疗效果的潜在机制。在这一系列实验中，我们将使用链脲佐菌素诱导的糖尿病大鼠和小鼠模型，并对心脏和内皮祖细胞进行全面的功能、分子和组织病理学检查。我们预计，这项提案中概述的实验结果将为糖尿病心衰的病理生理学特征以及创新的干细胞/祖细胞疗法在修复或预防糖尿病相关心肌损伤方面的应用提供新的见解。这些研究的成功完成将提供新的治疗策略，以解决一种临床疾病，这种疾病是造成主要发病率和死亡率的原因，而现有的临床治疗方法尚未充分解决这一问题。

DESCRIPTION (provided by applicant): Diabetes leads to myocardial dysfunction in the absence of coronary artery disease (CAD). This condition, diabetic cardiomyopathy (DCM), has been postulated to contribute to higher incidences of both congestive HF and mortality in diabetic patients. Even more serious is the occurrence, of HF following myocardial infarction (Ml) in long-standing diabetics, as diabetes induces adverse cardiac remodeling after Ml and leads to more severe HF. HF in diabetes with or without CAD (collectively referred to as diabetic HF) poses a major threat to public health as the incidence of diabetes rises, and as medical management prolongs the life span of diabetics. Despite these unique features of diabetic HF and the foreseen public health disaster due to the poor prognosis of diabetic HF, there have been no specific therapies targeting the principal pathophysiologic problems of diabetic heart diseases. We recently identified that impaired angiogenesis (formation of new vasculature from pre-existing mature endothelial cells) and decreased availability of circulating endothelial progenitor cells (EPCs) play a major role in the development of DCM. Recent identification of EPCs derived from adult bone marrow, which contribute to de novo development of vessels (vasculogenesis), has raised the possibility of utilizing these cells to repair ischemic/infarcted myocardium by inducing new vessel formation through the processes of vasculogenesis and angiogenesis. The long-term goal of this project is to define the role of the vasculature and its related biological factors in the development of diabetic HF and to establish more effective therapeutic strategies to treat diabetic HF. Accordingly, in this Proposal, we designed a series of experiments to investigate the role of angiogenesis and vasculogenesis in the development of diabetic HF and the impact of EPC transplantation on diabetic HF. In Specific Aim 1, we will investigate the role of defective myocardial angiogenesis and EPCs in the development of diabetic HF. In Specific Aim 2, we will explore the therapeutic impact of EPC transplantation on diabetic HF by using DCM and diabetic Ml models. In Specific Aim 3, we will investigate potential mechanisms which mediate the therapeutic effect of EPC transplantation. For this series of experiments, we will use streptozotocin-induced diabetic rat and mouse models and perform comprehensive functional, molecular and histopathologic examinations on the hearts and EPCs. We anticipate that the results of the experiments outlined in this proposal will yield new insight into the pathophysiologic features of diabetic HF and the application of innovative stem/progenitor cell therapy for repairing or preventing myocardial injury associated with diabetes. The successful completion of these studies should provide novel therapeutic strategies to address a clinical disorder that accounts for major morbidity and mortality and has to date been inadequately addressed by available clinical therapies.