Newly Published
Perioperative Medicine  |   November 2019
Transcription-independent Induction of ERBB1 through Hypoxia-inducible Factor 2A Provides Cardioprotection during Ischemia and Reperfusion
Author Notes
  • From the Department of Anesthesiology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas (J.W.L., J.L.B., X.Y., J.L., H.K.E.); Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany (M.K.); Department of Anesthesiology, University of New Mexico School of Medicine, Albuquerque, New Mexico (S.-W.S.); Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China (J.L.); Institute for Cancer Research, Department of Medicine, Medical University of Vienna, Vienna, Austria (M.S.); Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado (A.V.A.); Center for Clinical and Translational Sciences, The University of Texas Health Science Center at Houston, Houston, Texas (X.Z.); Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado (T.E.); and Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas (S.-H.Y.)
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • J.W.L. and M.K. contributed equally to this article.
    J.W.L. and M.K. contributed equally to this article.×
  • Submitted for publication October 8, 2018. Accepted for publication October 4, 2019.
    Submitted for publication October 8, 2018. Accepted for publication October 4, 2019.×
  • Correspondence: Address correspondence to Dr. Eltzschig: Center for Perioperative Medicine and Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St., MSB 5.020, Houston, Texas 77030. holger.eltzschig@uth.tmc.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Cardiovascular Anesthesia
Perioperative Medicine   |   November 2019
Transcription-independent Induction of ERBB1 through Hypoxia-inducible Factor 2A Provides Cardioprotection during Ischemia and Reperfusion
Anesthesiology Newly Published on November 26, 2019. doi:https://doi.org/10.1097/ALN.0000000000003037
Anesthesiology Newly Published on November 26, 2019. doi:https://doi.org/10.1097/ALN.0000000000003037
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury in the setting of myocardial ischemia.

  • In the setting of ischemia, myocyte-specific hypoxia-inducible factor 2A induces expression of amphiregulin, which is an epidermal growth factor that binds to epidermal growth factor receptor 1 (ERBB1) in the myocardium.

What This Article Tells Us That Is New:

  • This study found that hypoxia-inducible factor 2A enhances expression of epidermal growth factor receptor 1 (ERBB1) in the myocardium in the setting of ischemia. This leads to cardioprotection through activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling pathway.

Background: During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury.

Methods: Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury.

Results: Initial studies of myocardial tissues from patients with ischemic heart disease showed increased ERBB1 protein (1.12 ± 0.24 vs. 13.01 ± 2.20, P < 0.001). In contrast, ERBB1 transcript was unchanged. Studies using short hairpin RNA repression of Hif2A or Hif2aloxP/loxP Myosin Cre+ mice directly implicated hypoxia-inducible factor 2A in ERBB1 protein induction during hypoxia or after myocardial ischemia, respectively. Repression of RNA-binding protein 4 abolished hypoxia-inducible factor 2A–dependent induction of ERBB1 protein. Moreover, ErbB1loxP/loxP Myosin Cre+ mice experienced larger infarct sizes (22.46 ± 4.06 vs. 46.14 ± 1.81, P < 0.001) and could not be rescued via amphiregulin treatment.

Conclusions: These findings suggest that hypoxia-inducible factor 2A promotes transcription-independent induction of ERBB1 protein and implicates epidermal growth factor signaling in protection from myocardial ischemia and reperfusion injury.