title: 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 (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.
  
  
  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.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Qiumei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Monika
authors.initials: M
authors.lastname: Varga
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Haddad
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Songtao
authors.initials: S
authors.lastname: An
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Lejla
authors.initials: L
authors.lastname: Medzikovic
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Ronak
authors.initials: R
authors.lastname: Derakhshandeh
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Kostyushev
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Brian T
authors.initials: BT
authors.lastname: Clifford
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Emmy
authors.initials: E
authors.lastname: Luu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.).
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Danforth
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ (R.R., S.M.B.).
authors.forename: Ruslan
authors.initials: R
authors.lastname: Rafikov
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA (W.G., J.R.F.).
authors.forename: Wenhui
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Medicine, University of Arizona, Tucson, AZ (R.R., S.M.B.).
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.affiliation: I.M. Sechenov The First Moscow State Medical University, Moscow, Russia (S.V.S.).
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Suchkov
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.) Department of Pediatrics, University of California, San Francisco, San Francisco, CA (W.G., J.R.F.).
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.affiliation: Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA (K.A.).
authors.forename: Kirstin
authors.initials: K
authors.lastname: Aschbacher
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.) Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.) Eli & Edythe Broad Institute of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA (Y.Y., M.L.S.).
authors.forename: Yerem
authors.initials: Y
authors.lastname: Yeghiazarians
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA (Q.C., M.V., X.W., D.J.H., S.A., B.T.C., O.M.D., J.R.F., Y.Y., M.L.S.) Division of Cardiology, University of California, San Francisco, San Francisco, CA (L.M., R.D., D.S.K., Y.Z., E.L., C.H., Y.Y., M.L.S.) Eli & Edythe Broad Institute of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA (Y.Y., M.L.S.).
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Springer
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000201:enzymology*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000201:enzymology* / Q000637:transplantation*; D005260:Female; D006801:Humans; D008297:Male; D016513:Mice, SCID; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D020127:Recovery of Function; D012038:Regeneration; D015398:Signal Transduction; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: circulating angiogenic cells; endothelial progenitor cells; gene therapy; myocardial infarction; nitric oxide synthase