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C-src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction.

journal contribution
posted on 09.09.2014, 00:00 authored by 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
Objectives: the aim of this study was to evaluate the role of 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 Ecg monitoring, and inducibility studies. Tissues were collected for immunoblotting, Quantitative pcr, 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 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) than pp3 mice. Pp1 did not change infarct size, ecg 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.


National Institutes of Health grants P01 HL058000, R01 HL1024025, R01 HL106592, Veterans Administration Merit Award, and R41 HL112355 to SCD. National Center for Advancing Translational Sciences of the National Institute of Health TL1 TR000049 to CAR. National Institutes of Health R01 HL114395 and RO1 HL085369 to IRE. British Heart Foundation Travel Fellowship FS/11/69/29017 to FSN.


Publisher Statement

This is the author’s version of a work that was accepted for publication in Journal of the American College of Cardiology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in PUBLICATION, Vol 63, Issue 9, (Dec 14) DOI:10.1016/j.jacc.2013.10.081







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