Endothelial Progenitor Cell Targeting to Ischemic Myocardium Attenuates Hypoxia and Enhances Cardiomyocyte Viability and Function

Abstract

Introduction: Ischemic cardiomyopathy is a global health concern. Endothelial progenitor cell (EPC) upregulation with granulocyte-monocyte colony stimulating factor (GMCSF) followed by stromal-cell derived factor-1a (SDF) directed EPC chemokinesis is a means of myocardial revascularization.We recently reported upregulated EPCs, enhanced neovasculogenesis and increased myocardial perfusion with this therapy. To further investigate the biologic mechanisms we studied hypoxia attenuation, myocardial preservation, and function. Hypothesis: Neovasculogenic therapy with SDF/GMCSF enhances myocardial function by attenuating hypoxia and preserving myocardium. Methods: Lewis rats underwent LAD coronary ligation and progressed into heart failure. At 3wks the animals were randomized to intramyocardial SDF and subcutaneous GMCSF injections as therapy or saline as control. 6wks post-ligation borderzone vascular endothelial growth factor (VEGF) levels were quantified by western blot analysis. Endogenous VEGF is produced in response to tissue ischemia, thereby serving as a marker for hypoxia. Myocardial viability was determined by apoptosis as measured by caspase-3 activity levels and preservation of myocardial mass. Myocardial function was measured by echocardiography. Results: This therapy attenuated hypoxia as evidenced by decreased VEGF production. Enhanced myocardial preservation was noted by diminished apoptosis and enhanced myocardial to body mass ratio. There was a significant improvement in myocardial function with SDF/GMCSF therapy. Conclusions: GMCSF EPC upregulation and SDF mediated EPC chemokinesis enhances myocardial function by reversing myocardial ischemia and enhancing myocardial viability.