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.
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.
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