Molecular regulation of vascular stem cell function in ischemic heart failure

A balance between growth and apoptosis plays a critical role in maintaining the homeostasis of cardiovascular tissues.During the development of atherosclerosis and atherosclerosis-associated coronary heart disease many environmental factors exert regulatory effects on cardiovascular cells and their progenitors.We have recently investigated several proteins known to protect cells against ischemic damages.Here I would like to briefly review the literature and discuss with you some of our recent findings.Clusterin(CST) or named apolipoprotein-J is a stress-responding protein with multiple biological functions,including the inhibition of apoptosis and inflammation and transport of lipids.It may also participate in cell traffic and aggregation.In the process of post-infarct cardiac tissue repair,stem cells migrate into the damaged myocardium under the influence of chemoattractive substances such as stromal cell-derived factor(SDF).We tested whether CST enhances expression of stem cell homing receptor and migration of cardiac progenitor cells (CPCs).CPCs isolated from canine hearts transduced by CST cDNA expressed high levels of CXCR4,a receptor for SDF-1.The transfected cells also showed an increased migratory response to SDF-1 stimulation. The SDF-1-mediated migration of the CST-expressing CPCs was attenuated by PI3 kinase inhibitor LY294002,but not by mitogen-activated protein /ERK kinase inhibitor PD98059.Analysis of cell cycle by flow cytometry revealed no significant difference in cell cycle between the transduced and control CPCs.Thus,CST expression may increase CPCs migration via increasing CXCR4 expression and SDF-1/chemokine receptor signaling in a PI3/ Akt-dependent manner.The growth factor,erythropoietin (Epo),ameliorates the inflammatory response of the myocardium to ischemic injury.Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury.We studied the role of E-po in regulation of expression and activation of the cell death-associated intracellular signaling components i