Abstract 16103: Inhibition of c-Src Tyrosine Kinase Prevents Angiotensin II-Mediated Connexin43 Remodeling and Sudden Cardiac Death
Introduction: Renin-angiotensin system activation is associated with an increased risk of arrhythmia and sudden cardiac death (SCD); however, that mechanism is not well understood. The upregulation of c-Src by angiotensin II may result in the reduction of connexin43 (Cx43), which impairs gap junction function and provides a substrate for arrhythmia. We sought to test whether c-Src tyrosine kinase mediates Cx43 reduction and SCD in a transgenic mouse model of cardiac-restricted overexpression of angiotensin-converting enzyme (ACE8/8).
Method: Wild type and ACE8/8 mice with and without treatment with the c-Src inhibitor PP1 were studied. Telemetry monitoring, in vivo electrophysiology studies, Western blot analyses for total and phosphorylated c-Src and Cx43, immunohistochemistry staining for Cx43, and functional assessment of Cx43 with fluorescent dye diffusion were performed.
Results: The majority of the arrhythmic deaths resulted from ventricular tachycardia (VT) degenerating to ventricular fibrillation (83%) (Figure 1-B). Levels of total and phosphorylated c-Src were increased (1.4 and 2.6-fold, P < 0.05) and Cx43 reduced in ACE8/8 mice to 36% of the control (P < 0.05). PP1 reduced total and phospho c-Src levels, increased the Cx43 level by 2.1-fold at the gap junctions (P < 0.005), improved gap junctional communication (dye spread, P < 0.05), and reduced VT inducibility from 87% to 50% in ACE8/8 mice (P < 0.05) (figure 1-C). The survival rate increased from 11% to 86% with PP1 treatment (P < 0.005) (figure 1-A). Treatment with an inactive analog did not change survival or Cx43 levels.
Conclusion: Angiotensin II activation is associated with c-Src upregulation, Cx43 loss, reduced myocyte coupling, and SCD, which can be prevented by c-Src inhibition. This suggests that an increase in c-Src activity may help mediate angiotensin II induced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity.
- © 2011 by American Heart Association, Inc.