Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis

Background. Recent studies have reported that the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) can improve angiogenesis. Using an acute infarction model, we examined the therapeutic merit of statins on angiogenesis, alone and in combination with cell-based therapy. Methods. Zucker fatty rats, a strain characterized by obesity, hyperglycemia, and hyperlipidemia, were used for this study. After ligating the left anterior descending artery, rats were given oral pravastatin 5 or 50 mg/kg per day, or an intramyocardial injection of a total 2 x 10(7) autologous bone marrow mononuclear cells, or a combination of both. Cardiac function was assessed by echo-cardiography before treatment, then 7, 14, and 28 days after treatment. Histologic estimation of microvessel density, lymphocyte infiltration, and collagen fiber accumulation in the infarcted myocardium was performed 28 days after treatment. Results. Cardiac function was improved, and collagen deposition was decreased significantly after either cell implantation or pravastatin administration alone, but no synergistic effect was seen by their combination. However, microvessel density in the infarcted myocardium was increased only by implantation of bone marrow mononuclear cells, and not by administration of pravastatin. Pravastatin resulted in significant decreases in the serum levels of interleukin 1 beta and tumor necrosis factor-alpha, and also in the infiltration of CD45-positive cells, but not CD117-positive stem cells, in infarcted myocardium. Neither the number of circulating CD34-positive cells nor their endothelial differentiation potency was increased significantly 14 days after oral administration of pravastatin. Conclusions. Pravastatin can improve cardiac function after myocardial infarction, but through an antiinflammatory mechanism, rather than by induction of therapeutic angiogenesis. No synergistic effect for inducing angiogenesis was found by the combination of pravastatin and implantation of bone marrow mononuclear cells.