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, Kyusang Park, Young Kook Kim, Hyun Kook, Woo Jin Park, Tae Jin Lee, E. D. Abel, Jaetaek Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1183-1191
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number4
DOIs
Publication statusPublished - 2018 Apr 1

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Connexin 43
Tight Junctions
Cardiac Myocytes
Tamoxifen
Connexins
Atrial Natriuretic Factor
Transgenic Mice
Fibrosis
Heart Failure
Zonula Occludens-1 Protein
Injections
Mitochondrial Genes
Brain Natriuretic Peptide
Protein-Serine-Threonine Kinases
Knockout Mice
Hypertrophy
Protein Isoforms
Cell Death
Genotype
Insulin

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

Ock, Sangmi ; Lee, Wang Soo ; Kim, Hyun Min ; Park, Kyusang ; Kim, Young Kook ; Kook, Hyun ; Park, Woo Jin ; Lee, Tae Jin ; Abel, E. D. ; Kim, Jaetaek. / Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2018 ; Vol. 1864, No. 4. pp. 1183-1191.
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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.",
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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. / Ock, Sangmi; Lee, Wang Soo; Kim, Hyun Min; Park, Kyusang; Kim, Young Kook; Kook, Hyun; Park, Woo Jin; Lee, Tae Jin; Abel, E. D.; Kim, Jaetaek.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, No. 4, 01.04.2018, p. 1183-1191.

Research output: Contribution to journalArticle

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T1 - Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts

AU - Ock, Sangmi

AU - Lee, Wang Soo

AU - Kim, Hyun Min

AU - Park, Kyusang

AU - Kim, Young Kook

AU - Kook, Hyun

AU - Park, Woo Jin

AU - Lee, Tae Jin

AU - Abel, E. D.

AU - Kim, Jaetaek

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