Role of Angiogenesis and Endothelial Progenitor Cells in Diabetic Heart Failure

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， 糖尿病心肌病(DCM)被认为是导致充血性心力衰竭发生率较高的原因之一 糖尿病患者的死亡率。更严重的是心肌梗死后发生心力衰竭 (Ml)在长期糖尿病患者中，因为糖尿病在ml后引起不利的心脏重构，并导致更多 严重的心力衰竭。伴有或不伴有冠心病的糖尿病患者的心衰(统称为糖尿病心衰)对 随着糖尿病发病率的上升和医疗管理的延长， 糖尿病患者。尽管糖尿病心力衰竭的这些独特特征以及因穷人而导致的可预见的公共卫生灾难 糖尿病心衰的预后，目前还没有针对主要病理生理的特效治疗方法 糖尿病心脏病的问题。我们最近发现，血管生成受损(形成新的 来自预先存在的成熟内皮细胞的血管形成)和循环内皮细胞的可用性降低 祖细胞在扩张型心肌病的发生发展中起着重要作用。衍生内皮祖细胞的最新鉴定 来自成人骨髓，这有助于血管的新生发育(血管生成)，提高了 利用这些细胞通过诱导新血管形成修复缺血/梗死心肌的可能性 通过血管生成和血管生成的过程。 该项目的长期目标是确定血管系统及其相关生物因素在 研究糖尿病心衰的发展，并建立更有效的治疗策略。 因此，在这项提议中，我们设计了一系列实验来研究血管生成和 糖尿病心衰发展过程中的血管生成及EPC移植对糖尿病心衰的影响。在……里面 具体目标1，我们将研究缺陷心肌血管生成和内皮祖细胞在发育中的作用 糖尿病心力衰竭。在特定的目标2中，我们将探讨EPC移植对糖尿病心衰的治疗作用。 采用扩张型心肌病(DCM)和糖尿病大鼠模型。在具体目标3中，我们将研究潜在的机制 介导内皮祖细胞移植的疗效。对于这一系列实验，我们将使用 链脲佐菌素诱导的糖尿病大鼠和小鼠模型，并进行全面的功能，分子和 心脏和内皮祖细胞的组织病理学检查。我们预计实验的结果 这项建议将对糖尿病心衰的病理生理学特征和 干细胞/祖细胞疗法在修复或预防相关心肌损伤中的应用 患有糖尿病。这些研究的成功完成应该会提供新的治疗策略 解决一种导致重大发病率和死亡率的临床疾病，迄今仍不够充分 通过可用的临床疗法来解决。

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.