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Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult

  • Molecular and cellular mechanisms of disease
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Abstract

Several genetically modified mouse models implicated that prolyl-4-hydroxylase domain (PHD) enzymes are critical mediators for protecting tissues from an ischemic insult including myocardial infarction by affecting the stability and activation of hypoxia-inducible factor (HIF)-1 and HIF-2. Thus, the current efforts to develop small-molecule PHD inhibitors open a new therapeutic option for myocardial tissue protection during ischemia. Therefore, we aimed to investigate the applicability and efficacy of pharmacological HIFα stabilization by a small-molecule PHD inhibitor in the heart. We tested for protective effects in the acute phase of myocardial infarction after pre- or post-conditional application of the inhibitor. Application of the specific PHD inhibitor 2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate (ICA) resulted in HIF-1α and HIF-2α accumulation in heart muscle cells in vitro and in vivo. The rapid and robust responsiveness of cardiac tissue towards ICA was further confirmed by induction of the known HIF target genes heme oxygenase-1 and PHD3. Pre- and post-conditional treatment of mice undergoing myocardial infarction resulted in a significantly smaller infarct size. Tissue protection from ischemia after pre- or post-conditional ICA treatment demonstrates that there is a therapeutic time window for the application of the PHD inhibitor (PHI) post-myocardial infarction, which might be exploited for acute medical interventions.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft [M.V. is a fellow Ph.D. student of the IRTG1816] and an intramural grant from the University Erlangen Nürnberg (emerging field initiative: medicinal redox inorganic chemistry to N.B.).

Conflict of interest

There is no conflict of interest to be declared.

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    Authors and Affiliations

    1. Institute of Cardiovascular Physiology, University Medical Center, Georg-August-University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany

      Melanie Vogler, Anke Zieseniss, Amke R. Hesse & Dörthe M. Katschinski

    2. Institute of Pharmacology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany

      Elif Levent & Malte Tiburcy

    3. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Göttingen, Germany

      Anke Zieseniss, Amke R. Hesse, Elif Levent, Malte Tiburcy & Dörthe M. Katschinski

    4. Inorganic Chemistry and Organometallic Chemistry, Department of Chemistry and Pharmacy, Friedrich-Alexander-University, Erlangen, Germany

      Eva Heinze & Nicolai Burzlaff

    5. Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen, Germany

      Gunnar Schley, Kai Uwe Eckardt & Carsten Willam

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    1. Melanie Vogler
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    Correspondence to Dörthe M. Katschinski.

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    Melanie Vogler and Anke Zieseniss contributed equally.

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    Vogler, M., Zieseniss, A., Hesse, A.R. et al. Pre- and post-conditional inhibition of prolyl-4-hydroxylase domain enzymes protects the heart from an ischemic insult. Pflugers Arch - Eur J Physiol 467, 2141–2149 (2015). https://doi.org/10.1007/s00424-014-1667-z

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