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

血管紧张素 (1-7)：糖尿病心脏缺血的靶点

• 批准号: 7797462
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 34.05万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-08 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797462
• 关键词: AGTR2 gene; Accounting; Address; Adoptive Transfer; Adult; Adverse effects; Affect; Angioblast; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensins; Animals; Arteries; Attenuated; Biological; Biological Models; Blood; Blood flow; Bone Marrow; Bone Marrow Transplantation; Cardiac; Cardiovascular Physiology; Cardiovascular system; Cells; Cholesterol; Cicatrix; Coronary; Coronary artery; Dermal; Development; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Disease; Engraftment; Experimental Diabetes Mellitus; Healed; Heart; Heart Diseases; Heart failure; Hematopoietic; Home environment; Homing; Impaired wound healing; Individual; Infarction; Injection of therapeutic agent; Injury; Insulin-Dependent Diabetes Mellitus; Ischemia; Knock-out; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myelosuppression; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Oryctolagus cuniculus; Patients; Peptides; Performance; Play; Rattus; Recovery; Renin-Angiotensin System; Risk; Role; Site; Stem cells; Streptozocin; Survival Rate; Symptoms; Tissues; Transgenic Mice; Transplantation; Work; Wound Healing; angiogenesis; angiotensin I (1-7); angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; blood pressure regulation; db/db mouse; diabetic; healing; improved; interest; mortality; neovascularization; neovasculature; non-diabetic; overexpression; progenitor; public health relevance; receptor; receptor expression; repaired; research study; stem cell therapy; therapy development; type I and type II diabetes; vasculogenesis; wound

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.

描述（由申请人提供）： 缺血性心脏病被定义为冠状动脉狭窄和流向心脏的血液减少。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归因于潜在疾病对血液胆固醇水平的影响，但糖尿病患者中受损的伤口愈合通过损害受损组织的新血管形成而加剧和加速糖尿病性心脏病。干细胞治疗在心肌梗死后心脏损伤的修复中的应用已受到广泛关注。干细胞介导的糖尿病伤口和心脏组织中缺血的修复部分归因于受损组织的血管再生。具体地，源自骨髓的内皮祖细胞（EPC）介导受损组织中的新血管形成。糖尿病患者中受损的新血管形成可能归因于低分化的EPCs数量较少，这些EPCs的复制能力严重受损。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，并已变得特别令人感兴趣。特别地，Ang（1-7）的心血管作用抵消Ang II的心血管作用，并且其减弱心力衰竭的发展。我们已经证明，过继转移实验增强了用Ang-（1-7）预处理的辐射糖尿病受体小鼠中祖细胞的心脏植入。此外，Ang-（1-7）增加骨髓抑制个体中造血祖细胞的增殖，部分地通过加速新血管形成来增强糖尿病小鼠中的伤口愈合，并减小心肌梗死后瘢痕组织的大小。这些观察结果支持Ang-（1-7）在治疗糖尿病患者伤口组织新生血管能力降低导致的延迟愈合的疗法开发中的用途。本初始申请支持的工作的具体目标是使用Ang-（1-7）治疗糖尿病性心脏缺血性损伤，具体目标如下：具体目标1：我们将检测I型和II型糖尿病以及血管紧张素受体表达对祖细胞数量的影响以及A（1-7）促进移植祖细胞植入受辐射小鼠的能力。具体目标二：我们将研究Ang-（1-7）对新生血管形成和心脏性能的影响，以及骨髓祖细胞对梗死糖尿病小鼠的改善的贡献。具体目标3：我们将研究心肌特异性过表达Ang-（1-7）对糖尿病梗死小鼠祖细胞归巢和心功能的影响。 公共卫生相关性心脏缺血是与糖尿病相关的一种主要疾病，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。本申请的研究将评估Ang-（1-7）通过改善内皮祖细胞减少心肌梗死的能力，并鉴定其发生的分子机制。