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c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction
Cody A Rutledge1, Fu Siong Ng2, Matthew S Sulkin2
1Department of Physiology, University of Illinois at Chicago, Chicago, Illinois; Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island.
Objectives:
The aim of this study was to evaluate the role of tyrosine kinase cellular-Src (c-Src) inhibition on connexin43 (Cx43) regulation 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 current in ventricles. Activated c-Src has been linked to Cx43 dysregulation.
Methods:
MI was induced in 12-week-old mice by coronary artery occlusion. MI mice were treated with c-Src inhibitors (PP1 or AZD0530), PP3 (an inactive analogue of PP1), or saline. Treated hearts were compared to sham mice by echocardiography, optical mapping, telemetry electrocardiographic monitoring, and inducibility studies. Tissues were collected for immunoblotting, quantitative polymerase chain reaction, and immunohistochemistry.
Results:
Active c-Src was elevated in PP3-treated MI mice compared to sham at the scar border (280%, p = 0.003) and 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). PP1 raised Cx43 expression by 69% in the scar border (p = 0.048) and by 73% in the distal ventricle (p = 0.043) compared with 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) than PP3 mice. PP1 did not change infarct size, electrocardiographic pattern, or cardiac function. AZD0530 treatment demonstrated restoration of Cx43 comparable to PP1.
Conclusions:
c-Src inhibition improved Cx43 levels and conduction velocity and lowered arrhythmia inducibility after MI, suggesting a new approach for arrhythmia reduction following MI.
Insights
Cellular-Src (c-Src) inhibition improved connexin43 (Cx43) levels and conduction velocity in mice after myocardial infarction (MI). This approach shows promise for reducing arrhythmias post-MI.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- Myocardial infarction (MI) is linked to reduced expression of connexin43 (Cx43), crucial for ventricular electrical propagation.
- Activated cellular-Src (c-Src) kinase is implicated in Cx43 dysregulation following MI.
Purpose of the Study:
- To investigate the effect of c-Src inhibition on Cx43 regulation in a mouse model of MI.
- To assess the therapeutic potential of c-Src inhibitors in mitigating MI-induced cardiac abnormalities.
Main Methods:
- MI was induced in mice, followed by treatment with c-Src inhibitors (PP1 or AZD0530) or a control.
- Cardiac function, electrophysiology, and Cx43 expression were evaluated using echocardiography, optical mapping, and molecular techniques.
Main Results:
- c-Src inhibition (PP1) normalized elevated active c-Src levels and significantly increased Cx43 expression in MI hearts.
- Treatment restored conduction velocity and reduced ventricular arrhythmia inducibility.
- Infarct size and cardiac function remained unchanged.
Conclusions:
- Inhibition of c-Src effectively improves Cx43 levels and cardiac electrical properties after MI.
- Targeting c-Src represents a potential strategy for managing arrhythmias post-myocardial infarction.
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