Abstract Body: Background: Caveolin-1, a key inner plasma membrane scaffolding protein abundant in endothelial cells, cardiomyocytes, fibroblasts, and other cells, has been shown to regulate Connexin-43 and -40 (Cx-43, Cx-40) gap junction proteins. Recently, Cav-1 mutations, and the depletion of Cav-1, have been implicated in the development of atrial arrythmias. Cx-43 and Cx-40 are the two most abundantly expressed connexins in the atria. We hypothesized that Cav-1 depletion in endothelial cells may promote altered atrial gap junction function via altered expression of Cx-43 and Cx-40.
Methods: Four-to-six month-old male and female global knockout Cav-1 mice (gKO), and Cdh5.CreERT2 tamoxifen-inducible endothelial cell Cav-1 knockout (ecKO) mice were used to assess the role of Cav-1 depletion in atrial fibrillation. RT-qPCR was assessed to identify whether Cav-1 is an upstream regulator of connexin mRNA expression.
Results: In the left atrium, Cav-1 gKO mice, and ecKO mice experienced significantly decreased Cx-43 and Cx-40 mRNA expression relative to the WT controls (Figures A and B). In the right atrium, Cav-1 ecKO mice specifically experienced significantly decreased expression of Cx-43 and Cx-40 compared to the WT and gKO groups, suggesting a potential compensatory mechanism in the right atrium to maintain connexin integrity following the loss of Cav-1 from birth (Figured C and D). Statistical comparisons were conducted using One-Way-ANOVA for parametric variables with Tukey’s post hoc test for multiple comparisons.
Conclusion: Endothelial Cav-1 either directly or indirectly regulates mRNA expression levels of both Cx-40 and Cx-43 in the left and right atria. These findings suggest a potential crosstalk between endothelial Cav-1 and atrial gene regulatory networks implicating either the vasculature, or endocardium, as potential sites of connexin regulation via Cav-1.