Role of Angiogenesis and Endothelial Progenitor Cells in Diabetic Heart Failure

糖尿病在没有冠状动脉疾病（CAD）的情况下导致心肌功能障碍。这种情况， 糖尿病性心肌病（DCM）被认为是导致充血性心力衰竭（HF） 糖尿病患者的死亡率。更严重的是心肌梗死后HF的发生 (Ml)在长期糖尿病患者中，由于糖尿病在MI后诱导不良心脏重塑， 严重HF。糖尿病伴或不伴CAD的HF（统称为糖尿病HF）对以下疾病构成重大威胁： 随着糖尿病发病率的上升，以及医疗管理延长了患者的寿命， 糖尿病人尽管糖尿病HF具有这些独特的特征，并且由于贫困而可预见的公共卫生灾难 糖尿病HF的预后，目前还没有针对主要病理生理学的特异性治疗方法。 糖尿病性心脏病的问题。我们最近发现，受损的血管生成（新血管的形成）， 来自预先存在的成熟内皮细胞的血管）和循环内皮细胞的可用性降低。 祖细胞（EPCs）在DCM的发展中起主要作用。最近鉴定的EPCs来源于 从成人骨髓，这有助于从头发展的血管（血管发生），提高了 利用这些细胞通过诱导新血管形成来修复缺血/梗死心肌的可能性 通过血管生成和血管生成的过程。 本项目的长期目标是确定血管系统及其相关生物学因素在 探讨糖尿病心力衰竭的发病机制，建立更有效的治疗策略。 因此，在本提案中，我们设计了一系列实验来研究血管生成的作用， 糖尿病HF发展中的血管发生以及EPC移植对糖尿病HF的影响。在 具体目标1，我们将研究缺陷的心肌血管生成和EPCs在发展中的作用， 糖尿病HF在具体目标2中，我们将探讨EPC移植对糖尿病HF的治疗作用 通过使用DCM和糖尿病MI模型。在具体目标3中，我们将研究潜在的机制， 介导EPC移植的治疗作用。对于这一系列实验，我们将使用 链脲佐菌素诱导糖尿病大鼠和小鼠模型，并进行全面的功能，分子和 对心脏和EPCs进行组织病理学检查。我们预计实验结果 本提案中概述的方法将对糖尿病HF的病理生理学特征和 创新的干/祖细胞疗法在修复或预防心肌损伤中的应用 患有糖尿病这些研究的成功完成应该提供新的治疗策略， 解决一个临床疾病，占主要发病率和死亡率，迄今为止还没有充分 通过现有的临床治疗解决。

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.