Abstract 2430: c-Src Upregulation May Explain Connexin43 Remodeling in Renin-Angiotensin System Activation
Introduction: Elevated angiotensin II (AngII) is associated with increased arrhythmic risk, and pharmacology to reduce AngII signaling lessens that risk. We create a mouse model of renin-angiotensin system (RAS) activation by cardiac-restricted overexpression of angiotensin converting enzyme (ACE) achieved by replacing the ACE promoter with the α-MHC promoter. Homozygous ACE mice have elevated cardiac AngII and shown slow conduction, conduction blocks, ventricular tachycardia, and sudden death in the absence of structural heart disease. A major component of the ventricular gap junction complex, connexin43 (Cx43), is profoundly reduced in this model. Increases in c-Src are known to displace Cx43 from the intercalated disk with subsequent Cx43 degradation. We evaluated the role of c-Src in mediating the arrhythmic phenotype.
Method: After recorded the surface electrocardiography, performed an invasive electrophysiology study, and analyzed hearts from ACE and wild-type mice. The expression of Cx43 and c-Src were detected by immunoblotting.
Results: Compared with wild-type mice, ACE mice should increased arrhythmic inducibility and a 70% reduction in Cx43. Total cardiac c-Src was increased 2.6-fold (p<0.01) in ACE mice. Furthermore, the phospho-Src (Tyr416) was increased 6.1-fold (p<0.01). The ratio of phospho-Src to total Src was increased 2.1-fold (p<0.04). Transcriptional upregulation of c-Src may be explained by NFκB activation, a transcription factor shown to upregulate c-Src, whose nuclear localization was increases 5.1-fold in ACE mice (p<0.01).
Conclusions: Upregulation of tyrosine kinase, c-Src, in part by NFκB may explain the reduction in Cx43 and conduction in this model of RAS activation.
This research has received full or partial funding support from the American Heart Association, National Center.