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

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...

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Autores principales: Chen, Qiumei, Varga, Monika, Wang, Xiaoyin, Haddad, Daniel J., An, Songtao, Medzikovic, Lejla, Derakhshandeh, Ronak, Kostyushev, Dmitry S., Zhang, Yan, Clifford, Brian T., Luu, Emmy, Danforth, Olivia M., Rafikov, Ruslan, Gong, Wenhui, Black, Stephen M., Suchkov, Sergey V., Fineman, Jeffrey R., Heiss, Christian, Aschbacher, Kirstin, Yeghiazarians, Yerem, Springer, Matthew L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859354/
https://www.ncbi.nlm.nih.gov/pubmed/26738788
http://dx.doi.org/10.1161/JAHA.115.002257
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author Chen, Qiumei
Varga, Monika
Wang, Xiaoyin
Haddad, Daniel J.
An, Songtao
Medzikovic, Lejla
Derakhshandeh, Ronak
Kostyushev, Dmitry S.
Zhang, Yan
Clifford, Brian T.
Luu, Emmy
Danforth, Olivia M.
Rafikov, Ruslan
Gong, Wenhui
Black, Stephen M.
Suchkov, Sergey V.
Fineman, Jeffrey R.
Heiss, Christian
Aschbacher, Kirstin
Yeghiazarians, Yerem
Springer, Matthew L.
author_facet Chen, Qiumei
Varga, Monika
Wang, Xiaoyin
Haddad, Daniel J.
An, Songtao
Medzikovic, Lejla
Derakhshandeh, Ronak
Kostyushev, Dmitry S.
Zhang, Yan
Clifford, Brian T.
Luu, Emmy
Danforth, Olivia M.
Rafikov, Ruslan
Gong, Wenhui
Black, Stephen M.
Suchkov, Sergey V.
Fineman, Jeffrey R.
Heiss, Christian
Aschbacher, Kirstin
Yeghiazarians, Yerem
Springer, Matthew L.
author_sort Chen, Qiumei
collection PubMed
description 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.
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spelling pubmed-48593542016-05-20 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 Varga, Monika Wang, Xiaoyin Haddad, Daniel J. An, Songtao Medzikovic, Lejla Derakhshandeh, Ronak Kostyushev, Dmitry S. Zhang, Yan Clifford, Brian T. Luu, Emmy Danforth, Olivia M. Rafikov, Ruslan Gong, Wenhui Black, Stephen M. Suchkov, Sergey V. Fineman, Jeffrey R. Heiss, Christian Aschbacher, Kirstin Yeghiazarians, Yerem Springer, Matthew L. J Am Heart Assoc Original Research 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. John Wiley and Sons Inc. 2016-01-06 /pmc/articles/PMC4859354/ /pubmed/26738788 http://dx.doi.org/10.1161/JAHA.115.002257 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Chen, Qiumei
Varga, Monika
Wang, Xiaoyin
Haddad, Daniel J.
An, Songtao
Medzikovic, Lejla
Derakhshandeh, Ronak
Kostyushev, Dmitry S.
Zhang, Yan
Clifford, Brian T.
Luu, Emmy
Danforth, Olivia M.
Rafikov, Ruslan
Gong, Wenhui
Black, Stephen M.
Suchkov, Sergey V.
Fineman, Jeffrey R.
Heiss, Christian
Aschbacher, Kirstin
Yeghiazarians, Yerem
Springer, Matthew 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
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
title_full Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction
title_fullStr Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction
title_full_unstemmed Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction
title_short Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction
title_sort overexpression of nitric oxide synthase restores circulating angiogenic cell function in patients with coronary artery disease: implications for autologous cell therapy for myocardial infarction
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859354/
https://www.ncbi.nlm.nih.gov/pubmed/26738788
http://dx.doi.org/10.1161/JAHA.115.002257
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