Abstract
Diabetes Mellitus is a common disorder, with increasing risk of cardiac arrhythmias. Studies have shown that altered connexin expression and gap junction remodeling under hyperglycemia contribute to the high prevalence of cardiac arrhythmias and even sudden death. Connexin 43 (Cx43), a major protein that assembles to form cardiac gap junctions, has been found to be downregulated under high glucose conditions, along with inhibition of gap junctional intercellular communication (GJIC). While, apelin, a beneficial adipokine, increases Cx43 protein expression in mouse and human embryonic stem cells during cardiac differentiation. However, it remains unknown whether apelin influences GJIC capacity in cardiomyocytes. Here, using Western blotting and dye transfer assays, we found that Cx43 protein expression was reduced and GJIC was impaired after treatment with high glucose, which, however, could be abrogated after apelin treatment for 48 h. We also found that apelin increased Cx43 expression under normal glucose. Real-time PCR showed that the Cx43 mRNA was not significantly affected under high glucose conditions in the presence of apelin or high glucose and apelin. High glucose decreased the phosphorylation of AMPKα; however, apelin activated AMPKα. Interestingly, we found that Cx43 expression was increased after treatment with AICAR, an activator of AMPK signaling. AMPKα inhibition mediated with transfection of siRNA-AMPKα1 and siRNA-AMPKα2 abolished the protective effect of apelin on Cx43 expression. Our data suggest that apelin attenuates high glucose-induced Cx43 downregulation and improves the loss of functional gap junctions partly through the AMPK pathway.
Highlights
Diabetic cardiac dysfunction is characterized by mechanical and electrical abnormalities, which, in turn, result in a high prevalence of cardiac arrhythmias and sudden death [1]
Apelin ameliorates Connexin 43 (Cx43) reduction via AMPK in NRCMs and previous studies have reported that gap junctional intercellular communications (GJICs) are impaired and Cx43 expression is reduced in neonatal rat cardiomyocytes (NRCMs) exposed to high glucose [12, 13]
We aimed to identify the effects of apelin on the expression and function of gap junctions in NRCMs under high glucose treatment and to investigate whether AMPK was implicated in this condition
Summary
Diabetic cardiac dysfunction is characterized by mechanical and electrical abnormalities, which, in turn, result in a high prevalence of cardiac arrhythmias and sudden death [1]. Altered connexin expression and gap junction remodeling contribute to the high susceptibility of diabetic hearts to arrhythmias [2, 3]. Apelin ameliorates Cx43 reduction via AMPK in NRCMs and previous studies have reported that gap junctional intercellular communications (GJICs) are impaired and Cx43 expression is reduced in neonatal rat cardiomyocytes (NRCMs) exposed to high glucose [12, 13]. During cardiac differentiation of mouse and human embryonic stem cells, the increased expression of Cx43 was found in group treated with apelin [28]. It remains unclear whether apelin can treat arrhythmias. Several studies have demonstrated that Cx43 expression was regulated by AMPK activity [29, 33, 34]
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