Sex Differences in Cardiomyocyte Connexin43 Expression

Decreases in cardiac connexin43 (Cx43) play a critical role in abnormal cell-to-cell communication and have been linked to the resistance of the female heart to arrhythmias. We therefore hypothesized that Cx43 expression would be greater in female cardiomyocytes than in male cardiomyocytes under pathologic conditions. Adult ventricular myocytes were isolated from male and female rats and treated with phenylephrine (PE), a well-established pathologic stimulus. Cx43 gene and protein expression was determined. The expression of micro-RNA-1 (miR-1), a micro-RNA known to control Cx43 protein expression in cardiomyocytes, was also determined. Cx43 mRNA and protein levels were significantly higher in the female cardiomyocytes than in the male cardiomyocytes (mRNA: 1.4-fold; Protein: 5-fold, both P < 0.05) under both basal and pathologic conditions. PE treatment increased Cx43 expression only in female cardiomyocytes. Cx43 phosphorylation, a marker of preserved Cx43 function, was also higher (P < 0.05), and The expression of miR-1 was lower (P < 0.05) in the female cardiomyocytes after PE treatment. The expression of miR-1 was unchanged by PE treatment in male cardiomyocytes. Thus, a sex difference in miR-1 may be responsible for the sex difference in Cx43 expression in cardiomyocytes under pathologic conditions. Taken together, our results demonstrate a sex difference in Cx43 expression and site-specific phosphorylation that favors cardioprotection in female cardiomyocytes.