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

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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

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Cell- and Tissue-Based Therapy
Nitric Oxide Synthase
Coronary Artery Disease
Myocardial Infarction
Adenoviridae
Genetic Therapy
Nitric Oxide
Tissue Donors
Therapeutics
Nitric Oxide Synthase Type III
Vascular Endothelial Growth Factor A
Small Interfering RNA
Cell Movement
Volunteers
Blood Cells
Cardiovascular Diseases
Endothelial Cells
Animal Models
Complementary DNA
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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 Matthew; Suchkov, Sergey V.; Fineman, Jeffrey R.; Heiss, Christian; Aschbacher, Kirstin; Yeghiazarians, Yerem; Springer, Matthew L.

In: Journal of the American Heart Association, Vol. 5, No. 1, e002257, 01.01.2016.

Research output: Contribution to journalArticle

Chen, Q, Varga, M, Wang, X, Haddad, DJ, An, S, Medzikovic, L, Derakhshandeh, R, Kostyushev, DS, Zhang, Y, Clifford, BT, Luu, E, Danforth, OM, Rafikov, R, Gong, W, Black, SM, Suchkov, SV, Fineman, JR, Heiss, C, Aschbacher, K, Yeghiazarians, Y & Springer, ML 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, vol. 5, no. 1, e002257. https://doi.org/10.1161/JAHA.115.002257
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 Matthew ; 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. In: Journal of the American Heart Association. 2016 ; Vol. 5, No. 1.
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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.",
keywords = "Circulating angiogenic cells, Endothelial progenitor cells, Gene therapy, Myocardial infarction, Nitric oxide synthase",
author = "Qiumei Chen and Monika Varga and Xiaoyin Wang and Haddad, {Daniel J.} and Songtao An and Lejla Medzikovic and Ronak Derakhshandeh and Kostyushev, {Dmitry S.} and Yan Zhang and Clifford, {Brian T.} and Emmy Luu and Danforth, {Olivia M.} and Ruslan Rafikov and Wenhui Gong and Black, {Stephen Matthew} and Suchkov, {Sergey V.} and Fineman, {Jeffrey R.} and Christian Heiss and Kirstin Aschbacher and Yerem Yeghiazarians and Springer, {Matthew L.}",
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T1 - Overexpression of nitric oxide synthase restores circulating angiogenic cell function in patients with coronary artery disease

T2 - Implications for autologous cell therapy for myocardial infarction

AU - Chen, Qiumei

AU - Varga, Monika

AU - Wang, Xiaoyin

AU - Haddad, Daniel J.

AU - An, Songtao

AU - Medzikovic, Lejla

AU - Derakhshandeh, Ronak

AU - Kostyushev, Dmitry S.

AU - Zhang, Yan

AU - Clifford, Brian T.

AU - Luu, Emmy

AU - Danforth, Olivia M.

AU - Rafikov, Ruslan

AU - Gong, Wenhui

AU - Black, Stephen Matthew

AU - Suchkov, Sergey V.

AU - Fineman, Jeffrey R.

AU - Heiss, Christian

AU - Aschbacher, Kirstin

AU - Yeghiazarians, Yerem

AU - Springer, Matthew L.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

KW - Circulating angiogenic cells

KW - Endothelial progenitor cells

KW - Gene therapy

KW - Myocardial infarction

KW - Nitric oxide synthase

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