Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction

Abstract

Background Circulating angiogenic cells ( CAC s) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease ( CAD ) impairs the therapeutic potential of CAC s for myocardial infarction ( MI ) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide ( NO ) synthase ( eNOS ) overcomes these defects. Methods and Results We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CAC s to well‐established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CAC s to endothelial tubes, eNOS mRNA and protein levels, and  NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI . The high‐function isolates substantially improved cardiac function, whereas the low‐function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post‐ MI mice implanted with the CAC s. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. Conclusions Age and CAD impair multiple functions of CAC s and limit therapeutic potential for the treatment of MI . eNOS gene therapy in CAC s from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.