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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.

journal of the american heart association

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