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Journal of the American Heart Association, volume 5, issue 1

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

Chen Qiumei 1
An Songtao 1
Wang Xiaoyin 1
Varga Mónika 1
Luu Emmy 2
Derakhshandeh Ronak 2
Suchkov Sergey V. 3
Medzikovic Lejla 2
Clifford Brian T. 1
Danforth Olivia M. 1
Gong Wenhui 4
Aschbacher Kirstin 5
Yeghiazarians Yerem 1, 2, 6
Black Stephen M. 7
Zhang Yan 2
Haddad Daniel J. 1
Varga Monika 1
Zhang Yan 2
Rafikov Ruslan 7
Fineman Jeffrey R. 1, 4
Heiss Christian 2
Springer Matthew L. 1, 2, 6
1
 
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
2
 
Division of Cardiology, University of California, San Francisco, San Francisco, CA
4
 
Department of Pediatrics, University of California, San Francisco, San Francisco, CA
5
 
Department of Psychiatry, University of California, San Francisco, San Francisco, CA
6
 
Eli & Edythe Broad Institute of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA
7
 
Department of Medicine, University of Arizona, Tucson, AZ
Publication typeJournal Article
Publication date2016-01-13
Quartile SCImago
Q1
Quartile WOS
Q2
Impact factor5.4
ISSN20479980
Cardiology and Cardiovascular Medicine
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.

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Elsevier
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1
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GOST Copy
Chen Q. et al. 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. 2016. Vol. 5. No. 1.
GOST all authors (up to 50) Copy
Varga M., Zhang Y., Haddad D. J., Black S. M., Yeghiazarians Y., Aschbacher K., Suchkov S. V., Gong W., Danforth O. M., Luu E., Clifford B. T., Derakhshandeh R., Medzikovic L., An S., Wang X., Chen Q., Varga M., Kostyushev D., Zhang Y., Rafikov R., Fineman J. R., Heiss C., Springer M. L. 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. 2016. Vol. 5. No. 1.
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RIS Copy
TY - JOUR
DO - 10.1161/JAHA.115.002257
UR - https://doi.org/10.1161%2FJAHA.115.002257
TI - Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction
T2 - Journal of the American Heart Association
AU - Chen, Qiumei
AU - Varga, Mónika
AU - Wang, Xiaoyin
AU - An, Songtao
AU - Medzikovic, Lejla
AU - Derakhshandeh, Ronak
AU - Clifford, Brian T.
AU - Luu, Emmy
AU - Danforth, Olivia M.
AU - Gong, Wenhui
AU - Suchkov, Sergey V.
AU - Aschbacher, Kirstin
AU - Yeghiazarians, Yerem
AU - Black, Stephen M.
AU - Haddad, Daniel J.
AU - Zhang, Yan
AU - Varga, Monika
AU - Kostyushev, Dmitry
AU - Zhang, Yan
AU - Rafikov, Ruslan
AU - Fineman, Jeffrey R.
AU - Heiss, Christian
AU - Springer, Matthew L.
PY - 2016
DA - 2016/01/13 00:00:00
PB - Wiley
IS - 1
VL - 5
PMID - 26738788
SN - 2047-9980
ER -
BibTex
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BibTex Copy
@article{2016_Chen,
author = {Qiumei Chen and Mónika Varga and Xiaoyin Wang and Songtao An and Lejla Medzikovic and Ronak Derakhshandeh and Brian T. Clifford and Emmy Luu and Olivia M. Danforth and Wenhui Gong and Sergey V. Suchkov and Kirstin Aschbacher and Yerem Yeghiazarians and Stephen M. Black and Daniel J. Haddad and Yan Zhang and Monika Varga and Dmitry Kostyushev and Yan Zhang and Ruslan Rafikov and Jeffrey R. Fineman and Christian Heiss and Matthew L. Springer},
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},
journal = {Journal of the American Heart Association},
year = {2016},
volume = {5},
publisher = {Wiley},
month = {jan},
url = {https://doi.org/10.1161%2FJAHA.115.002257},
number = {1},
doi = {10.1161/JAHA.115.002257}
}
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