Decreased KCNE2 Expression Participates in the Development of Cardiac Hypertrophy by Regulation of Calcineurin-NFAT (Nuclear Factor of Activated T Cells) and Mitogen-Activated Protein Kinase Pathways.

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  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101479941 Publication Model: Print Cited Medium: Internet ISSN: 1941-3297 (Electronic) Linking ISSN: 19413289 NLM ISO Abbreviation: Circ Heart Fail Subsets: MEDLINE
    • Publication Information:
      Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins
    • Subject Terms:
      Gene Expression Regulation*; Calcineurin/*genetics ; Cardiomegaly/*genetics ; Mitogen-Activated Protein Kinases/*metabolism ; NFATC Transcription Factors/*genetics ; Potassium Channels, Voltage-Gated/*genetics ; RNA/*genetics; Animals ; Animals, Newborn ; Apoptosis ; Calcineurin/metabolism ; Cardiomegaly/metabolism ; Disease Models, Animal ; Humans ; Immunohistochemistry ; Myocardium/metabolism ; Myocardium/pathology ; NFATC Transcription Factors/metabolism ; Polymerase Chain Reaction ; Potassium Channels, Voltage-Gated/biosynthesis ; Rats ; Rats, Sprague-Dawley
    • Abstract:
      Background: KCNE2 is a promiscuous auxiliary subunit of voltage-gated cation channels. A recent work demonstrated that KCNE2 regulates L-type Ca 2+ channels. Given the important roles of altered Ca 2+ signaling in structural and functional remodeling in diseased hearts, this study investigated whether KCNE2 participates in the development of pathological hypertrophy.
      Methods and Results: We found that cardiac KCNE2 expression was significantly decreased in phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes and in transverse aortic constriction-induced cardiac hypertrophy in mice, as well as in dilated cardiomyopathy in human. Knockdown of KCNE2 in neonatal rat ventricular myocytes reproduced hypertrophy by increasing the expression of ANP (atrial natriuretic peptide) and β-MHC (β-myosin heavy chain), and cell surface area, whereas overexpression of KCNE2 attenuated phenylephrine-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased intracellular Ca 2+ transient, calcineurin activity, and nuclear NFAT (nuclear factor of activated T cells) protein levels, and pretreatment with inhibitor of L-type Ca 2+ channel (nifedipine) or calcineurin (FK506) attenuated the activation of calcineurin-NFAT pathway and cardiomyocyte hypertrophy. Meanwhile, the phosphorylation levels of p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were increased, and inhibiting the 3 cascades of mitogen-activated protein kinase reduced cardiomyocyte hypertrophy induced by KCNE2 knockdown. Overexpression of KCNE2 in heart by ultrasound-microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and mitogen-activated protein kinase pathways in transverse aortic constriction mice.
      Conclusions: This study demonstrates that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin-NFAT and mitogen-activated protein kinase pathways. Targeting KCNE2 is a potential therapeutic strategy for the treatment of hypertrophy.
      (© 2017 American Heart Association, Inc.)
    • Comments:
      Retraction in: Circ Heart Fail. 2017 Nov;10 (11):. (PMID: 29141855)
    • Grant Information:
      R01 HL130346 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: animals; calcineurin; calcium; hypertrophy; mice
    • Accession Number:
      0 (KCNE2 protein, human)
      0 (NFATC Transcription Factors)
      0 (Potassium Channels, Voltage-Gated)
      63231-63-0 (RNA)
      EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
      EC 3.1.3.16 (Calcineurin)
    • Publication Date:
      Date Created: 20170615 Date Completed: 20170809 Latest Revision: 20180119
    • Publication Date:
      20240829
    • Accession Number:
      10.1161/CIRCHEARTFAILURE.117.003960
    • Accession Number:
      28611128