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

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Matthew L. Springer¹  Daniel J. Haddad¹  Monika Varga¹  Jeffrey R. Fineman¹  Songtao An¹  Yerem Yeghiazarians¹  Brian T. Clifford¹  Xiaoyin Wang¹  Olivia M. Danforth¹  Qiumei Chen¹  Ruslan Rafikov²  Stephen M. Black²  Wenhui Gong³  Kirstin Aschbacher⁴  Lejla Medzikovic⁵  Dmitry S. Kostyushev⁵  Ronak Derakhshandeh⁵  Emmy Luu⁵  Christian Heiss⁵  Yan Zhang⁵  Sergey V. Suchkov⁶ 

[1] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA;Department of Medicine, University of Arizona, Tucson, AZ;Department of Pediatrics, University of California, San Francisco, San Francisco, CA;Department of Psychiatry, University of California, San Francisco, San Francisco, CA;Division of Cardiology, University of California, San Francisco, San Francisco, CA;I.M. Sechenov The First Moscow State Medical University, Moscow, Russia;

关键词: circulating angiogenic cells;    endothelial progenitor cells;    gene therapy;    myocardial infarction;    nitric oxide synthase;   

DOI  :  10.1161/JAHA.115.002257

来源: DOAJ

【 摘 要 】

BackgroundCirculating angiogenic cells (CACs) 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 CACs 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 ResultsWe recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs 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 CACs 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 CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. ConclusionsAge and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.

【 授权许可】

Unknown