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

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, Akt2 mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1 mice to generate the following genotypes:Akt1; Akt2 (WT), Akt2; α-MHC-MCM (iAkt2 KO), Akt1, and Akt1; Akt2; 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.

Estrogen-Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats

“…This hypothesis is also supported by the reduction in phosphorylated (p)-AKT levels in the hearts of these rats (Fig. 5D) and by the association of reduced cardiac p-AKT with disrupted gap junction proteins and cardiac contractile dysfunction (Ock et al, 2018).…”

Vinpocetine Protects Against Cerebral Ischemia-Reperfusion Injury by Targeting Astrocytic Connexin43 via the PI3K/AKT Signaling Pathway

“…A previous study showed that PI3K/AKT plays a crucial role in modulating Cx43 expression (Bhattacharjee et al, 2009), conveying mechanical signals to the Cx43 hemichannel and mediating its opening in osteocytes (Batra et al, 2014). Besides, Cx43 has been shown to decrease expression in the heart of AKT1 −/− /iAKT2 knockout mice, revealing that AKT plays an important role in maintaining systolic function and Cx43 protein stability (Ock et al, 2018). Inhibition of the PI3K/AKT pathway by LY294002 can reduce Cx43 expression and block the cardioprotective effect of atorvastatin (Bian et al, 2015).…”

Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models

“…However, in two insulin resistance models based on primary rat CM, lipid overload has also been demonstrated to generate functional alterations which may have implications in DCM, such as contractile dysfunction [62, 64]. The same effect on contractility was also achieved by repressing Akt1 and Akt2 expression in rat neonatal CMs [65]. High uric acid-induced insulin resistance could be reversed by an antioxidant, indicating a mechanism of insulin resistance through oxidative stress [63].…”