Systemic pretreatment with dimethyloxalylglycine increases myocardial HIF-1α and VEGF production and improves functional recovery after acute ischemia/reperfusion

Jeffrey A. Poynter, Mariuxi Manukyan, Yue Wang, Benjamin D. Brewster, Jeremy L. Herrmann, Brent R. Weil, Aaron M. Abarbanell, Daniel R. Meldrum

Research output: Contribution to journalArticle

Abstract

Background: Stem cells protect the heart from ischemic damage in part by the release of cytoprotective growth factors, particularly vascular endothelial growth factor (VEGF). Production of VEGF is regulated in part by levels of the transcription factor hypoxia inducible factor 1-α (HIF-1α). Dimethyloxalylglycine (DMOG) prevents the deactivation of HIF-1α and increases VEGF production. However, the effects of systemic DMOG treatment on myocardial tolerance for ischemia are unknown. We hypothesized that systemic pretreatment with DMOG would improve myocardial ischemic tolerance. Methods: To study this hypothesis, adult male rats were randomly given an intraperitoneal injection of DMOG (40 mg/kg in 1 mL saline, n = 5) or saline (1 mL, n = 6) 24 h before cardiectomy and isolated heart perfusion. All hearts were subjected to 15 min equilibration, 25 min ischemia and 40 min reperfusion. Myocardial function was continuously monitored. Following reperfusion, myocardial homogenates were analyzed for HIF-1α and VEGF production. Results: We observed that hearts in the DMOG group exhibited greater recovery of left ventricular developed pressure LVDP, +dP/dt and -dP/dt. Myocardial HIF-1α and VEGF levels were increased by DMOG therapy. Conclusion: In conclusion, systemic pretreatment with DMOG augments post-ischemic myocardial functional recovery through increased HIF-1α levels and greater VEGF production.

Original languageEnglish (US)
Pages (from-to)278-283
Number of pages6
JournalSurgery
Volume150
Issue number2
DOIs
StatePublished - Aug 2011
Externally publishedYes

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Hypoxia-Inducible Factor 1
Vascular Endothelial Growth Factor A
Reperfusion
Ischemia
Ventricular Pressure
oxalylglycine
Intraperitoneal Injections
Myocardial Ischemia
Intercellular Signaling Peptides and Proteins
Transcription Factors
Stem Cells
Perfusion
Therapeutics

ASJC Scopus subject areas

  • Surgery

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Systemic pretreatment with dimethyloxalylglycine increases myocardial HIF-1α and VEGF production and improves functional recovery after acute ischemia/reperfusion. / Poynter, Jeffrey A.; Manukyan, Mariuxi; Wang, Yue; Brewster, Benjamin D.; Herrmann, Jeremy L.; Weil, Brent R.; Abarbanell, Aaron M.; Meldrum, Daniel R.

In: Surgery, Vol. 150, No. 2, 08.2011, p. 278-283.

Research output: Contribution to journalArticle

Poynter, Jeffrey A. ; Manukyan, Mariuxi ; Wang, Yue ; Brewster, Benjamin D. ; Herrmann, Jeremy L. ; Weil, Brent R. ; Abarbanell, Aaron M. ; Meldrum, Daniel R. / Systemic pretreatment with dimethyloxalylglycine increases myocardial HIF-1α and VEGF production and improves functional recovery after acute ischemia/reperfusion. In: Surgery. 2011 ; Vol. 150, No. 2. pp. 278-283.
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abstract = "Background: Stem cells protect the heart from ischemic damage in part by the release of cytoprotective growth factors, particularly vascular endothelial growth factor (VEGF). Production of VEGF is regulated in part by levels of the transcription factor hypoxia inducible factor 1-α (HIF-1α). Dimethyloxalylglycine (DMOG) prevents the deactivation of HIF-1α and increases VEGF production. However, the effects of systemic DMOG treatment on myocardial tolerance for ischemia are unknown. We hypothesized that systemic pretreatment with DMOG would improve myocardial ischemic tolerance. Methods: To study this hypothesis, adult male rats were randomly given an intraperitoneal injection of DMOG (40 mg/kg in 1 mL saline, n = 5) or saline (1 mL, n = 6) 24 h before cardiectomy and isolated heart perfusion. All hearts were subjected to 15 min equilibration, 25 min ischemia and 40 min reperfusion. Myocardial function was continuously monitored. Following reperfusion, myocardial homogenates were analyzed for HIF-1α and VEGF production. Results: We observed that hearts in the DMOG group exhibited greater recovery of left ventricular developed pressure LVDP, +dP/dt and -dP/dt. Myocardial HIF-1α and VEGF levels were increased by DMOG therapy. Conclusion: In conclusion, systemic pretreatment with DMOG augments post-ischemic myocardial functional recovery through increased HIF-1α levels and greater VEGF production.",
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AU - Manukyan, Mariuxi

AU - Wang, Yue

AU - Brewster, Benjamin D.

AU - Herrmann, Jeremy L.

AU - Weil, Brent R.

AU - Abarbanell, Aaron M.

AU - Meldrum, Daniel R.

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AB - Background: Stem cells protect the heart from ischemic damage in part by the release of cytoprotective growth factors, particularly vascular endothelial growth factor (VEGF). Production of VEGF is regulated in part by levels of the transcription factor hypoxia inducible factor 1-α (HIF-1α). Dimethyloxalylglycine (DMOG) prevents the deactivation of HIF-1α and increases VEGF production. However, the effects of systemic DMOG treatment on myocardial tolerance for ischemia are unknown. We hypothesized that systemic pretreatment with DMOG would improve myocardial ischemic tolerance. Methods: To study this hypothesis, adult male rats were randomly given an intraperitoneal injection of DMOG (40 mg/kg in 1 mL saline, n = 5) or saline (1 mL, n = 6) 24 h before cardiectomy and isolated heart perfusion. All hearts were subjected to 15 min equilibration, 25 min ischemia and 40 min reperfusion. Myocardial function was continuously monitored. Following reperfusion, myocardial homogenates were analyzed for HIF-1α and VEGF production. Results: We observed that hearts in the DMOG group exhibited greater recovery of left ventricular developed pressure LVDP, +dP/dt and -dP/dt. Myocardial HIF-1α and VEGF levels were increased by DMOG therapy. Conclusion: In conclusion, systemic pretreatment with DMOG augments post-ischemic myocardial functional recovery through increased HIF-1α levels and greater VEGF production.

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