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Research ArticleCardiovascular

Prolyl-Hydroxylase Inhibition Preserves Endothelial Cell Function in a Rat Model of Vascular Ischemia Reperfusion Injury

Enikő Barnucz, Gábor Veres, Péter Hegedűs, Stephanie Klein, Raphael Zöller, Tamás Radovits, Sevil Korkmaz, Ferenc Horkay, Béla Merkely, Matthias Karck and Gábor Szabó
Journal of Pharmacology and Experimental Therapeutics April 2013, 345 (1) 25-31; DOI: https://doi.org/10.1124/jpet.112.200790
Enikő Barnucz
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Gábor Veres
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Péter Hegedűs
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Stephanie Klein
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Raphael Zöller
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Tamás Radovits
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Sevil Korkmaz
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Ferenc Horkay
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Béla Merkely
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Matthias Karck
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Gábor Szabó
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany (E.B., G.V., P.H., S.Kl., R.Z., S.Ko., M.K., G.S.); and Heart and Vascular Center, Semmelweis University, Budapest, Hungary (E.B., G.V., P.H., T.R., F.H., B.M.)
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Abstract

Storage protocols of vascular grafts need further improvement against ischemia-reperfusion (IR) injury. Hypoxia elicits a variety of complex cellular responses by altering the activity of many signaling pathways, such as the oxygen-dependent prolyl-hyroxylase domain–containing enzyme (PHD). Reduction of PHD activity during hypoxia leads to stabilization and accumulation of hypoxia inducible factor (HIF) 1α. We examined the effects of PHD inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMCs) in a model of cold ischemia/warm reperfusion. Aortic segments underwent 24 hours of cold ischemic preservation in saline or DMOG (dimethyloxalylglycine)-supplemented saline solution. We investigated endothelium-dependent and -independent vasorelaxations. To simulate IR injury, hypochlorite (NaOCl) was added during warm reperfusion. VSMCs were incubated in NaCl or DMOG solution at 4°C for 24 hours after the medium was changed for a supplied standard medium at 37°C for 6 hours. Apoptosis was assessed using the TUNEL method. Gene expression analysis was performed using quantitative real-time polymerase chain reaction. Cold ischemic preservation and NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95% ± 1% versus NaOCl 44% ± 4% versus DMOG 68% ± 5%). Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl group, and DMOG treatment significantly decreased apoptosis. Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group. Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function. Inhibition of PHDs could therefore be a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR injury.

Footnotes

    • Received October 7, 2012.
    • Accepted February 5, 2013.
  • This work was supported by the Land Baden-Württemberg; the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (to T.R.); the National Development Agency of Hungary [TÁMOP-4.2.2-08/1/KMR-2008-004, TÁMOP-4.2.2/B-10/1-2010-0013]; and the Medical Faculty of the University of Heidelberg (to S.K.).

  • dx.doi.org/10.1124/jpet.112.200790.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 345 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 345, Issue 1
1 Apr 2013
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Research ArticleCardiovascular

Prolyl-Hydroxylase Inhibition Preserves Endothelial Function

Enikő Barnucz, Gábor Veres, Péter Hegedűs, Stephanie Klein, Raphael Zöller, Tamás Radovits, Sevil Korkmaz, Ferenc Horkay, Béla Merkely, Matthias Karck and Gábor Szabó
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 25-31; DOI: https://doi.org/10.1124/jpet.112.200790

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Research ArticleCardiovascular

Prolyl-Hydroxylase Inhibition Preserves Endothelial Function

Enikő Barnucz, Gábor Veres, Péter Hegedűs, Stephanie Klein, Raphael Zöller, Tamás Radovits, Sevil Korkmaz, Ferenc Horkay, Béla Merkely, Matthias Karck and Gábor Szabó
Journal of Pharmacology and Experimental Therapeutics April 1, 2013, 345 (1) 25-31; DOI: https://doi.org/10.1124/jpet.112.200790
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