Angiotensin(1-7): A Target in Diabetic Cardiac Ischemia

描述（由申请人提供）：缺血性心脏病的定义是冠状动脉狭窄和流向心脏的血流量减少。在糖尿病患者中，缺血性心脏病是发病率和死亡率的重要原因。虽然糖尿病性心脏缺血的风险增加部分可归因于潜在疾病对血液胆固醇水平的影响，但糖尿病患者伤口愈合受损会通过损害受损组织的新生血管来加剧和加速糖尿病性心脏病。在心肌梗死后心脏损伤的修复中，干细胞疗法的应用受到了广泛的重视。干细胞介导的糖尿病伤口和心脏组织缺血修复部分归因于受损组织的血运重建。具体来说，来自骨髓的内皮祖细胞（EPC）介导受损组织中的新生血管。糖尿病患者的新生血管受损可能是由于低分化EPCs数量减少，其复制能力严重受损。肾素-血管紧张素系统（RAS）在心脏和血压控制中起着关键作用。除了血管紧张素（Ang） II外，其他Ang肽，如Ang-(1-7)也具有重要的生物活性，并已成为人们特别关注的问题。特别是，Ang（1-7）的心血管作用抵消了Ang II的作用，并减轻了心力衰竭的发展。我们已经证明，过继性转移实验增强了经Ang-预处理的辐照糖尿病受体小鼠的祖细胞心脏植入（1-7）。此外，Ang-(1-7)在骨髓抑制个体中增加造血祖细胞的增殖，促进糖尿病小鼠的伤口愈合，部分通过加速新生血管形成，并减少心肌梗死后疤痕组织的大小。这些观察结果支持Ang-(1-7)用于治疗糖尿病患者伤口组织新生血管能力下降导致的延迟愈合的疗法开发。这项初步应用支持的工作的具体目标是，直接使用Ang-(1-7)治疗糖尿病性心脏缺血损伤：具体目标1：我们将研究I型和II型糖尿病和血管紧张素受体表达对祖细胞数量和A（1-7）促进移植祖细胞植入辐照小鼠的能力的影响。具体目标2：我们将研究Ang-(1-7)对梗死糖尿病小鼠新生血管和心脏功能的影响，以及骨髓祖细胞对改善梗死糖尿病小鼠的贡献。特异性目的3：我们将研究心肌特异性过表达Ang-(1-7)对梗死糖尿病小鼠祖细胞归巢和心功能的影响。心脏缺血是与糖尿病相关的主要疾病，可导致心肌梗死。这可能部分是由于内皮祖细胞数量和功能的减少。本应用研究将评估Ang-(1-7)通过改善内皮祖细胞减少心肌梗死的能力，并确定其发生的分子机制。

DESCRIPTION (provided by applicant): Ischemic heart disease is defined as the narrowing of the coronary arteries and decreased blood flow to the heart. In diabetics, ischemic heart disease represents a significant cause of morbidity and mortality. While increased risk for diabetic cardiac ischemia is partially attributable to the effect of the underlying disease on the levels of blood cholesterol, impaired wound healing in diabetics exacerbates and accelerates diabetic heart disease by impairing neovascularization of damaged tissue. Much emphasis has been placed on the use of stem cell therapy for the repair of heart damage induced after myocardial infarction. Stem cell-mediated repair of ischemia in diabetic wounds and cardiac tissue is attributable, in part, to revascularization of damaged tissue. Specifically, endothelial progenitor cells (EPC) arising from the bone marrow mediate neovascularization in damaged tissue. Impaired neovascularization in diabetics may be attributed to lower numbers of poorly differentiated EPCs that are severely impaired in their capacity to replicate. The renin- angiotensin system (RAS) plays a critical role in cardiac and blood pressure control. In addition to angiotensin (Ang) II, other Ang peptides, such as Ang-(1-7) also have important biological activities and has become of particular interest. In particular, the cardiovascular actions of Ang (1-7) counteract those of Ang II and it attenuates the development of heart failure. We have demonstrated that adoptive transfer experiments enhance cardiac engraftment of progenitors in irradiated diabetic recipient mice pre-treated with Ang-(1-7). In addition, Ang-(1-7) increases proliferation of hematopoietic progenitors in myelosuppressed individuals, enhances wound healing in diabetic mice, partly through accelerated neovascularization, and reduces the size of the scar tissue after myocardial infarction. These observations support the use of Ang-(1-7) in the development of therapies to treat delayed healing resulting from a diminished ability to neovascularize wound tissue in diabetics. The specific aims for the work supported by this initial application, which are directed to the use of Ang-(1-7) in the treatment of diabetic cardiac ischemic injury are as follows: Specific Aim 1: We will examine the effect of type I and type II diabetes and angiotensin receptor expression on progenitor number and ability of A(1-7) to promote engraftment of transplanted progenitor cells into irradiated mice. Specific Aim 2: We will examine the effect of Ang-(1-7) on neovascularization, and cardiac performance and the contribution of bone marrow progenitors to the improvement in infarcted diabetic mice. Specific Aim 3: We will examine the effect of cardiac-specific overexpression of Ang-(1-7) on progenitor cell homing and cardiac function in infarcted diabetic mice. PUBLIC HEALTH RELEVANCE Cardiac ischemia is a major morbidity associated with diabetes through contributing to myocardial infarction. This may be, in part, due to a reduction in number and function of endothelial progenitor cells. Studies in this application will evaluate the ability of Ang-(1-7) to reduce cardiac infarction through improving endothelial progenitor cells and to identify the molecular mechanisms by which this occurs.