Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

Sangmi Ock; Wang Soo Lee; Hyun Min Kim; Kyu-Sang Park; Young-Kook Kim; Hyun Kook; Woo Jin Park; Tae Jin Lee; E.D Abel; Jaetaek Kim

doi:10.1016/j.bbadis.2018.01.022

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Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

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Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

Sangmi Ock, Wang Soo Lee, Hyun Min Kim, Kyu-Sang Park, Young-Kook Kim, Hyun Kook, Woo Jin Park, Tae Jin Lee, E.D Abel and Jaetaek Kim

Biochimica et biophysica acta. Molecular basis of disease, Vol.1864(4), pp.1183-1191

04/2018

DOI: 10.1016/j.bbadis.2018.01.022

PMCID: PMC6342503

PMID: 29378301

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Abstract

While deletion of Akt1 results in a smaller heart size and Akt2−/− mice are mildly insulin resistant, Akt1−/−/Akt2−/− mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, Akt2flox/flox mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1−/− mice to generate the following genotypes:Akt1+/+; Akt2flox/flox (WT), Akt2flox/flox; α-MHC-MCM (iAkt2 KO), Akt1−/−, and Akt1−/−; Akt2flox/flox; α-MHC-MCM mice (Akt1−/−/iAkt2 KO). At 28 days after the first tamoxifen injection, Akt1−/−/iAkt2 KO mice developed contractile dysfunction paralleling increased atrial and brain natriuretic peptide (ANP and BNP) levels, and repressed mitochondrial gene expression. Neither cardiac fibrosis nor apoptosis were detected in Akt1−/−/iAkt2 KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3 days after the first tamoxifen injection, Akt1−/−/iAkt2 KO hearts showed decreased expression of connexin43 (Cx43) and connexin-interacting protein zonula occludens-1 (ZO-1). Furthermore, Akt1/2 silencing significantly decreased both Cx43 and ZO-1 expression in cultured neonatal rat cardiomyocytes in concert with reduced beating frequency. Akt1 and Akt2 are required to maintain cardiac contraction. Loss of Akt signaling disrupts gap junction protein, which might precipitate early contractile dysfunction prior to heart failure in the absence of myocardial remodeling, such as hypertrophy, fibrosis, or cell death. •Cardiac Akt1-/-/iAkt2 KO in mice reduces cardiac size and induces contractile dysfunction without myocardial remodeling.•Akt1-/-/iAkt2 KO hearts revealed decreased expression of Cx43 and connexin-interacting protein ZO-1.•Akt isoforms may play important roles to maintain cardiac contractile function through gap junction protein stability.

Heart Failure

Akt isoforms

Gap junction

Details

Title: Subtitle: Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts
Creators: Sangmi Ock - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
Wang Soo Lee - Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
Hyun Min Kim - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
Kyu-Sang Park - Department of Physiology, Yonsei University Wonju College of Medicine, Wonjoo, Republic of Korea
Young-Kook Kim - Department of Biochemistry, Chonnam National University Medical School, Gwangju, Republic of Korea
Hyun Kook - Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea
Woo Jin Park - Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
Tae Jin Lee - Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
E.D Abel - Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Jaetaek Kim - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta. Molecular basis of disease, Vol.1864(4), pp.1183-1191
DOI: 10.1016/j.bbadis.2018.01.022
PMID: 29378301
PMCID: PMC6342503
NLM abbreviation: Biochim Biophys Acta Mol Basis Dis
ISSN: 0925-4439
eISSN: 1879-260X
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/501100003725, name: National Research Foundation of Korea, award: 2009-0077202, 2016R1A4A1009895; DOI: 10.13039/100000002, name: National Institutes of Health, award: U01 HL087947
Language: English
Date published: 04/2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024529402771

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