Downregulation of connexin 43 gene expression in rat heart during inflammation. The role of tumour necrosis factor

Abstract

Gap junctions form channels that mediate the communication between adjacent cells. Alterations in gap junction function and/or expression are believed to contribute to cardiac dysfunction such as those observed in septic patients. The expression of connexin 43 (Cx43), the subunit component of the most abundant cardiac gap junction, was analysed in rat heart during inflammation induced by the administration of bacterial lipopolysaccharide (LPS). Cx43 mRNA levels were found to be dramatically (>50%) and rapidly (2 h) reduced in the heart after injection of LPS (1 mg/kg). To investigate the possible mechanism of the decrease in Cx43 expression during inflammation, the promoter region of this gene was cloned. The basal Cx43 promoter activity was observed within 224-134 bp of the transcriptional initiation site after transfection into a rat myoblast cell-line (H9c2). The Cx43 promoter activity was found to be reduced by incubation of the transfected cells with serum obtained from LPS-treated rats. Moreover, Cx43 promoter activity was also decreased upon incubation with tumour necrosis factor alpha. These results suggest that Cx43 expression in the heart can be modulated by circulating cytokines. These observations may have important implications in the depression of heart function observed in septic patients.