thymosin-beta(4) and Coronary-Disease

Despite recent advances in the treatment of coronary heart disease, a significant number of patients progressively develop heart failure. Reduction of infarct size after acute myocardial infarction and normalization of microvasculature in chronic myocardial ischemia could enhance cardiac survival.. Induction of neovascularization using vascular growth factors has emerged as a promising novel approach for cardiac regeneration. Thymosin β4 (Tβ4) might be a promising candidate for the treatment of ischemic heart disease. It has been characterized as a major G-actin-sequestering factor regulating cell motility, migration, and differentiation. During cardiac development, Thymosin β4 seems essential for vascularization of the myocardium. In the adult organism, Thymosin β4 has anti-inflammatory properties, increases myocyte and endothelial cell survival accompanied by differentiation of epicardial progenitor cells. In chronic myocardial ischemia, Tβ4 overexpression enhances micro- and macrovasculature in the ischemic area and thereby improves myocardial function. A comparable effect is seen in diabetic and dyslipidemic pig ischemic hearts, suggesting an attractive therapeutic potential of adeno-associated virus encoding for Tβ4 for patients with ischemic heart disease.. Induction of mature micro-vessels is a prerequisite for chronic myocardial ischemia and might be achieved via a long-term overexpression of Thymosin β4.

Topics: Adult; Animals; Cardiotonic Agents; Cell Survival; Coronary Disease; Cytoprotection; Heart; Humans; Myocardium; Myocytes, Cardiac; Swine; Thymosin

Ischemic heart disease leading to myocardial infarction causes irreversible cell loss and scarring and is a major cause of morbidity and mortality in humans. Significant effort in the field of cardiovascular medicine has been invested in the search for adult cardiac progenitor cells that may replace damaged muscle cells and/or contribute to new vessel formation (neovascularization) and in the identification of key factors, which may induce such progenitor cells to contribute to myocardial repair and collateral vessel growth. We recently demonstrated that the actin monomer-binding protein, thymosin beta-4 (Tbeta-4), when secreted from the myocardium provides a paracrine stimulus to the cells of the epicardium-derived cells (EPDCs) to promote their inward migration and differentiation into endothelial and smooth muscle cells to form the coronary vasculature. Translating this essential role for Tbeta-4 in coronary vessel development to the adult, we found that treatment of cultured adult explants with Tbeta-4 stimulated extensive outgrowth of epicardin-positive epicardial cells, which, as they migrated away from the explant, differentiated into procollagen type I, SMalphaA, and Flk1-positive cells indicative of fibroblasts, smooth muscle, and endothelial cells; thus releasing the adult epicardium from a quiescent state and restoring pluripotency. The ability of Tbeta-4 to promote coronary vessel development and potentially induce new vasculature in the adult is essential for cardiomyocyte survival and could contribute significantly toward the reported Tbeta4-induced cardioprotection and repair in the adult heart. Tbeta-4 is currently subject to multicenter phase 1 clinical trials for treatment of cardiovascular disease (http://www.regenerx.com), therefore, insight into the repair mechanism(s) induced by Tbeta-4 is an essential step toward harnessing therapeutic survival, migration, and repair properties of the peptide in the context of acute myocardial damage.

Topics: Animals; Coronary Disease; Coronary Vessels; Heart; Mice; Neovascularization, Pathologic; Pericardium; Thymosin

Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.. This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus.. Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 ± 14 c/hpf in db vs. 234 ± 8 c/hpf in wt hearts; p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls; p < 0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p < 0.05). Treatment with rAAV.Tβ4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV.VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV.Tβ4 but not rAAV.VEGF-A improved EF in db hearts (34.5 ± 1.4%), but less so than in wt hearts (44.8 ± 1.5%).. Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.

Topics: Animals; Coronary Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Genetic Therapy; Heart Failure; Heart Transplantation; Humans; Microvessels; Myocardial Stunning; Myocardium; Neovascularization, Physiologic; Stroke Volume; Swine; Thymosin; Translational Research, Biomedical; Vascular Endothelial Growth Factor A