c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction.

Abstract

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.

• Authors: Cody A Rutledge, Fu Siong Ng, Matthew S Sulkin, Ian D Greener, Artem M Sergeyenko, Hong Liu, Joanna Gemel, Eric C Beyer, Ali A Sovari, Igor R Efimov, Samuel C Dudley
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 63 Issue 9 Pg. 928-34 (Mar 11 2014) ISSN: 1558-3597 [Electronic] United States
• PMID: 24361364 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzodioxoles
• Connexin 43
• Enzyme Inhibitors
• Quinazolines
• Reactive Oxygen Species
• saracatinib
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• Protein Phosphatase 1

Topics

• Animals
• Arrhythmias, Cardiac (metabolism, physiopathology)
• Benzodioxoles (pharmacology)
• CSK Tyrosine-Protein Kinase
• Connexin 43 (metabolism)
• Death, Sudden
• Echocardiography
• Enzyme Inhibitors (pharmacology)
• Gap Junctions (metabolism)
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (metabolism, physiopathology)
• Protein Phosphatase 1 (metabolism)
• Quinazolines (pharmacology)
• Reactive Oxygen Species (metabolism)
• src-Family Kinases (antagonists & inhibitors)