Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8258582 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2018 | 31 Pages |
Abstract
While deletion of Akt1 results in a smaller heart size and Akt2â/â mice are mildly insulin resistant, Akt1â/â/Akt2â/â 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 Akt1â/â mice to generate the following genotypes:Akt1+/+; Akt2flox/flox (WT), Akt2flox/flox; α-MHC-MCM (iAkt2 KO), Akt1â/â, and Akt1â/â; Akt2flox/flox; α-MHC-MCM mice (Akt1â/â/iAkt2 KO). At 28â¯days after the first tamoxifen injection, Akt1â/â/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 Akt1â/â/iAkt2 KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3â¯days after the first tamoxifen injection, Akt1â/â/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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Authors
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,