Lithium promotion of connexin43 protein in infarcted rats by Wnt‐ and PI3K/Akt‐dependent GSK‐3β phosphorylation signaling

The purpose of this study was to determine whether lithium can attenuate arrhythmias through increasing GSK‐3β/β‐catenin‐induced connexin43 by activating Wnt and phosphoinositide‐3 kinase (PI3K)/Akt after myocardial infarction. Male Wistar rats were subjected to coronary artery ligation and then randomized to either saline or lithium treatment for 4 weeks. Myocardial connexin43 levels were significantly decreased in the saline‐treated infarcted rats compared with sham. These attenuated connexin43 levels were blunted after lithium. Arrhythmic scores during programmed stimulation in the lithium‐treated infarcted rats were significantly lower than those treated with the saline‐treated infarcted rats. Lithium increased Akt phosphorylation 4.5‐fold in the border zone compared to saline after infarction. The two downstream targets of Akt, phosphorylated GSK‐3β and nuclear translocated β‐catenin were significantly increased by 11.2‐fold and 3.6‐fold, respectively. Inhibition of Wnt and PI3K/Akt signaling prevented GSK‐3β phosphorylation as well as β‐catenin nuclear translocation, and blocked the beneficial effects of lithium on connexin43 phosphorylation. Chronic use of lithium after infarction, resulting in enhanced connexin43 levels through both Wnt‐ and PI3K/Akt‐dependent GSK‐3β pathways may attenuate the arrhythmogenic response to programmed electrical stimulation.