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Nat Commun. 2018 Feb 26;9(1):816. doi: 10.1038/s41467-018-03105-2.

Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury.

Author information

1
Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany. Michael.koeppen@med.uni-tuebingen.de.
2
Department of Anaesthesiology, Ludwig-Maximilians-University, Muenchen, Germany. Michael.koeppen@med.uni-tuebingen.de.
3
Department of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA.
4
Department of Anesthesiology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
5
Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
6
Department of Anaesthesiology, Ludwig-Maximilians-University, Muenchen, Germany.
7
Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
8
Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, USA.

Abstract

Myocardial ischemia-reperfusion injury (IRI) leads to the stabilization of the transcription factors hypoxia-inducible factor 1-alpha (HIF1-alpha) and hypoxia-inducible factor 2-alpha (HIF2-alpha). While previous studies implicate HIF1-alpha in cardioprotection, the role of HIF2-alpha remains elusive. Here we show that HIF2-alpha induces the epithelial growth factor amphiregulin (AREG) to elicit cardioprotection in myocardial IRI. Comparing mice with inducible deletion of Hif1a or Hif2a in cardiac myocytes, we show that loss of Hif2-alpha increases infarct sizes. Microarray studies in genetic models or cultured human cardiac myocytes implicate HIF2-alpha in the myocardial induction of AREG. Likewise, AREG increases in myocardial tissues from patients with ischemic heart disease. Areg deficiency increases myocardial IRI, as does pharmacologic inhibition of Areg signaling. In contrast, treatment with recombinant Areg provides cardioprotection and reconstitutes mice with Hif2a deletion. These studies indicate that HIF2-alpha induces myocardial AREG expression in cardiac myocytes, which increases myocardial ischemia tolerance.

PMID:
29483579
PMCID:
PMC5827027
DOI:
10.1038/s41467-018-03105-2
[Indexed for MEDLINE]
Free PMC Article

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