Abstract 14640: c-Src Kinase Inhibition Reduces Arrhythmia Inducibility and Connexin43 Dysregulation After Myocardial Infarction
Objectives: The aim of this study was to evaluate the effect of pharmacological inhibition of c-Src tyrosine kinase on connexin43 (Cx43) remodeling in a mouse model of myocardial infarction (MI).
Background: MI is associated with decreased expression of Cx43, the principal gap junction protein responsible for propagating electrical current in ventricles. Activated c-Src has been linked to Cx43 dysregulation by destabilizing gap junction proteins.
Methods: Coronary artery occlusion was performed on 12-week-old mice causing MI. MI mice were treated with c-Src inhibitors PP1 and AZD0530 as well as PP3, an inactive analogue, and saline. Treated hearts were compared functionally to sham mice by echocardiography, optical mapping, telemetry ECG monitoring, and inducibility studies. Tissues were collected for Western blot analysis, quantitative PCR, and immunohistochemistry.
Results: Active c-Src was elevated in MI mice treated with inactive PP3 when compared to sham at the scar border (280%, p=0.003) and the distal ventricle (346%, p=0.013). PP1 treatment restored active c-Src to sham levels at the scar border (86%, p=0.95) and distal ventricle (94%, p=1.0). c-Src inhibition by PP1 raised Cx43 expression 69% in the scar border (p=0.048) and 73% in the distal ventricle (p=0.043) compared to PP3 mice. PP1-treated mice had restored conduction velocity at the scar border (PP3: 32 cm/s, PP1: 41 cm/s, p < 0.05) and lower arrhythmic inducibility (PP3: 71%, PP1: 35%, p < 0.05) compared to PP3 mice. PP1 did not change infarct size, ECG pattern, or cardiac function. AZD0530 treatment, a c-Src inhibitor in clinical development, demonstrated c-Src inhibition and restoration of Cx43 comparable to PP1.
Conclusions: c-Src inhibition improves Cx43 levels and conduction velocity and lowers arrhythmia inducibility after MI, suggesting a new approach for arrhythmia reduction following MI.
- © 2013 by American Heart Association, Inc.