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: 7462238
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 35.72万
• 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/7462238
• 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 Models; 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; Localized; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myelosuppression; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Oryctolagus cuniculus; Patients; Peptides; Performance; Play; Protein Overexpression; Public Health; Rate; Rattus; Recovery; Renin-Angiotensin System; Risk; Role; Site; Stem cells; Streptozocin; Survival Rate; Symptoms; Tissues; Transgenic Mice; Transplantation; Tumor-Associated Vasculature; Work; Wound Healing; angiogenesis; angiotensin I (1-7); angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; blood pressure regulation; day; db/db mouse; diabetic; healing; improved; interest; mortality; neovascularization; non-diabetic; progenitor; receptor; receptor expression; repaired; research study; size; 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）：缺血性心脏病的定义是冠状动脉的狭窄和血液流向心脏的缩小。在糖尿病患者中，缺血性心脏病代表了发病率和死亡率的重要原因。尽管增加的糖尿病性心脏缺血风险部分归因于潜在疾病对血液胆固醇水平的影响，糖尿病患者的伤口愈合受损会加剧伤口，并通过损害受损组织的新血管化来加速糖尿病心脏病。在使用干细胞疗法来修复心肌梗死后诱发的心脏损伤上，已经非常重视。干细胞介导的糖尿病伤口缺血和心脏组织中缺血的修复是可归因于受损组织的血运重建。具体而言，由骨髓引起的内皮祖细胞（EPC）介导受损组织中的新血管形成。糖尿病患者的新血管形成受损可能归因于较低的分化不良的EPC，这些EPC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至关重要的作用。除了血管紧张素（ANG）II之外，其他ANG肽（例如Ang-（1-7））也具有重要的生物学活性，并且已经特别感兴趣。特别是，ANG（1-7）的心血管作用抵消了Ang II的心血管动作，并削弱了心力衰竭的发展。我们已经证明，收养转移实验可以增强用Ang-预处理的糖尿病患者小鼠的祖细胞的心脏植入（1-7）。此外，Ang-（1-7）增加了骨髓抑制个体中造血祖细胞的增殖，增强了糖尿病小鼠的伤口愈合，部分通过加速的新血管形成，并减少心肌梗塞后疤痕组织的大小。这些观察结果支持使用Ang-（1-7）在疗法开发中的使用，以治疗由于糖尿病患者中伤口组织的伤口组织的能力降低而导致的延迟愈合。该初步应用支持的工作的具体目的是针对Ang-（1-7）在治疗糖尿病心脏缺血性损伤治疗中的特定目的如下：具体目的1：我们将研究I型糖尿病和血管紧张素受体表达的影响，以及（1-7）对（1-7）促进植物植入物的祖细胞数量和能力的影响。具体目标2：我们将研究Ang-（1-7）对新血管形成，心脏性能以及骨髓祖细胞对梗塞糖尿病小鼠改善的影响。具体目标3：我们将研究Ang-（1-7）心脏特异性过表达对梗塞糖尿病小鼠祖细胞归纳和心脏功能的影响。 公共卫生相关性心脏缺血是与糖尿病有关的主要发病率，通过促进心肌梗塞。这可能部分是由于内皮祖细胞的数量和功能减少。该应用中的研究将评估Ang-（1-7）通过改善内皮祖细胞减少心脏梗塞的能力，并确定发生这种情况的分子机制。