PMID- 29483579
OWN - NLM
STAT- MEDLINE
DCOM- 20181121
LR  - 20190926
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 9
IP  - 1
DP  - 2018 Feb 26
TI  - Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens 
      myocardial ischemia-reperfusion injury.
PG  - 816
LID - 10.1038/s41467-018-03105-2 [doi]
LID - 816
AB  - 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.
FAU - Koeppen, Michael
AU  - Koeppen M
AD  - Department of Anaesthesiology and Intensive Care Medicine, Tubingen University 
      Hospital, Eberhard-Karls University Tubingen, Tubingen, Germany. 
      Michael.koeppen@med.uni-tuebingen.de.
AD  - Department of Anaesthesiology, Ludwig-Maximilians-University, Muenchen, Germany. 
      Michael.koeppen@med.uni-tuebingen.de.
FAU - Lee, Jae W
AU  - Lee JW
AD  - Department of Anesthesiology, The University of Texas Health Science Center at 
      Houston, McGovern Medical School, Houston, TX, USA.
FAU - Seo, Seong-Wook
AU  - Seo SW
AD  - Department of Anesthesiology, University of New Mexico School of Medicine, 
      Albuquerque, NM, USA.
FAU - Brodsky, Kelley S
AU  - Brodsky KS
AD  - Division of Cardiology, Department of Medicine, University of Colorado School of 
      Medicine, Aurora, CO, USA.
FAU - Kreth, Simone
AU  - Kreth S
AD  - Department of Anaesthesiology, Ludwig-Maximilians-University, Muenchen, Germany.
FAU - Yang, Ivana V
AU  - Yang IV
AD  - Division of Pulmonary Science and Critical Care Medicine, Department of Medicine, 
      University of Colorado School of Medicine, Aurora, CO, USA.
FAU - Buttrick, Peter M
AU  - Buttrick PM
AD  - Division of Cardiology, Department of Medicine, University of Colorado School of 
      Medicine, Aurora, CO, USA.
FAU - Eckle, Tobias
AU  - Eckle T
AD  - Department of Anesthesiology, University of Colorado School of Medicine, Aurora, 
      CO, USA.
FAU - Eltzschig, Holger K
AU  - Eltzschig HK
AD  - Department of Anesthesiology, The University of Texas Health Science Center at 
      Houston, McGovern Medical School, Houston, TX, USA.
LA  - eng
GR  - R01 HL122472/HL/NHLBI NIH HHS/United States
GR  - R01 DK097075/DK/NIDDK NIH HHS/United States
GR  - R01 HL133900/HL/NHLBI NIH HHS/United States
GR  - P01 HL114457/HL/NHLBI NIH HHS/United States
GR  - R01 HL119837/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180226
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Amphiregulin)
RN  - 0 (Areg protein, mouse)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.7.7.- (Cre recombinase)
RN  - EC 2.7.7.- (Integrases)
RN  - EC 3.6.4.1 (Myosins)
SB  - IM
MH  - Amphiregulin/*genetics/metabolism/pharmacology
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/antagonists & 
      inhibitors/*genetics/metabolism
MH  - Cell Line
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & 
      inhibitors/*genetics/metabolism
MH  - Integrases/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Microarray Analysis
MH  - Myocardial Reperfusion Injury/*genetics/metabolism/pathology/prevention & control
MH  - Myocardium/*metabolism/pathology
MH  - Myocytes, Cardiac/drug effects/*metabolism/pathology
MH  - Myosins/genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
PMC - PMC5827027
COIS- The authors declare no competing financial interests.
EDAT- 2018/02/28 06:00
MHDA- 2018/11/22 06:00
PMCR- 2018/02/26
CRDT- 2018/02/28 06:00
PHST- 2015/10/15 00:00 [received]
PHST- 2018/01/19 00:00 [accepted]
PHST- 2018/02/28 06:00 [entrez]
PHST- 2018/02/28 06:00 [pubmed]
PHST- 2018/11/22 06:00 [medline]
PHST- 2018/02/26 00:00 [pmc-release]
AID - 10.1038/s41467-018-03105-2 [pii]
AID - 3105 [pii]
AID - 10.1038/s41467-018-03105-2 [doi]
PST - epublish
SO  - Nat Commun. 2018 Feb 26;9(1):816. doi: 10.1038/s41467-018-03105-2.