Cx43 overexpression reduce the incidence of obstructive sleep apnea associated atrial fibrillation via the CaMKⅡγ/HIF-1 axis

Abstract

Background: Previous studies by our group have demonstrated chronic intermittent hypoxia (CIH) can decrease connexin 43 (Cx43) protein expression and thus increase atrial fibrillation (AF) inducibility. Cardiac sympathetic denervation (CSD) can reduce AF and increase Cx43 expression, however, the underlying molecular mechanisms and signaling pathways are still unclear.

Methods and results: An obstructive sleep apnea (OSA) rat model in vivo experiments and CIH H9c2 cells model in vitro experiments were used to figure out the roles and underlying mechanisms of Cx43 on OSA-associated AF. In this study, we examined the expression of Cx43, CaMKⅡγ, Bax, Caspase 3, HIF-1 Bcl-2, Tunel, and CPB/p300, to discover the association between proteins and the mechanism of regulatory changes. The downstream proteins of Cx43 were calculated by gene sequencing and data analysis. We found Cx43 expression was significantly downregulated after CIH exposure in rat and H9c2 cells. Active caspase-3 and Bax at CIH+8 h group are high, but decreased at OE+8 h group. The Bcl-2 expression was higher in the N and OE+8 h group than CIH+8 h group. TUNEL-positive cells from the CIH+8 h group was markedly higher. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated Cx43 overexpression inhibited the CaMKIIγ expression, and CaMKIIγ was involved in the HIF-1 signaling pathway. In addition, we also found Cx43 overexpression remarkably decreased the HIF-1 protein and p300 mRNA expression, which inhibits the CaMKIIγ/HIF-1 signaling pathway.

Conclusions: Taken together, these results suggested Cx43 overexpression inhibits the expression of calcium/calmodulin dependent protein CaMKⅡγ via the Cx43/CaMKIIγ/HIF-1 axis, which finally reduces the myocardial apoptosis and incidence of AF.

Keywords: Atrial fibrillation; CaMKⅡγ; Chronic intermittent hypoxia; Cx43; Obstructive sleep apnea.