Overexpression of nitric oxide synthase restores circulating angiogenic cell function in patients with coronary artery disease: Implications for autologous cell therapy for myocardial infarction

Qiumei Chen, Monika Varga, Xiaoyin Wang, Daniel J. Haddad, Songtao An, Lejla Medzikovic, Ronak Derakhshandeh, Dmitry S. Kostyushev, Yan Zhang, Brian T. Clifford, Emmy Luu, Olivia M. Danforth, Ruslan Rafikov, Wenhui Gong, Stephen Matthew Black, Sergey V. Suchkov, Jeffrey R. Fineman, Christian Heiss, Kirstin Aschbacher, Yerem YeghiazariansMatthew L. Springer

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background-Circulating 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 Results-We 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. Conclusions-Age 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.

Original languageEnglish (US)
Article numbere002257
JournalJournal of the American Heart Association
Volume5
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

  • Circulating angiogenic cells
  • Endothelial progenitor cells
  • Gene therapy
  • Myocardial infarction
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Chen, Q., Varga, M., Wang, X., Haddad, D. J., An, S., Medzikovic, L., Derakhshandeh, R., Kostyushev, D. S., Zhang, Y., Clifford, B. T., Luu, E., Danforth, O. M., Rafikov, R., Gong, W., Black, S. M., Suchkov, S. V., Fineman, J. R., Heiss, C., Aschbacher, K., ... Springer, M. L. (2016). 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, 5(1), [e002257]. https://doi.org/10.1161/JAHA.115.002257