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Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt A):1183-1191. doi: 10.1016/j.bbadis.2018.01.022. Epub 2018 Jan 31.

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

Author information

1
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
2
Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
3
Department of Physiology, Yonsei University Wonju College of Medicine, Wonjoo, Republic of Korea.
4
Department of Biochemistry, Chonnam National University Medical School, Gwangju, Republic of Korea.
5
Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
6
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
7
Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
8
Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA, USA. Electronic address: DRCAdmin@uiowa.edu.
9
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. Electronic address: jtkim@cau.ac.kr.

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.

KEYWORDS:

Akt isoforms; Gap junction; Heart failure

PMID:
29378301
PMCID:
PMC6342503
DOI:
10.1016/j.bbadis.2018.01.022
[Indexed for MEDLINE]
Free PMC Article

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