Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that
correlate with cardiac contractile dysfunction in Akt deficient hearts.
Authors Ock S, Lee WS, Kim HM, Park KS, Kim YK, Kook H, Park WJ, Lee TJ, Abel ED, Kim J
Submitted By E. Dale Abel on 6/5/2018
Status Published
Journal Biochimica et biophysica acta
Year 2018
Date Published
Volume : Pages 1864 : 1183 - 1191
PubMed Reference 29378301
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;
a-MHC-MCM (iAkt2 KO), Akt1-/-, and Akt1-/-; Akt2flox/flox; a-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.

Investigators with authorship
E. Dale AbelUniversity of Iowa