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

Journal of the American College of Cardiology
Cody A RutledgeSamuel C Dudley

Abstract

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). 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. 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. 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 vel...Continue Reading

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Citations

Aug 5, 2015·Future Cardiology·Michael G Fradley, Javier Pinilla-Ibarz
Jun 21, 2015·Cellular and Molecular Life Sciences : CMLS·Merlijn J MeensHeather S Duffy
Mar 4, 2015·Journal of Electrocardiology·Narcis TribulovaCsilla Viczenczova
Jan 15, 2014·Journal of the American College of Cardiology·Luisa Mestroni, Duy Thai Nguyen
Sep 22, 2017·Pharmacological Reviews·Luc LeybaertRainer Schulz
Nov 3, 2017·BioMed Research International·Aiming WuLimin Chai
Sep 22, 2020·Journal of Molecular and Cellular Cardiology·Li ZhengPaul L Sorgen
Nov 4, 2020·Trends in Molecular Medicine·Tania Martins-MarquesHenrique Girao
Jul 30, 2021·The Journal of Clinical Investigation·Man LiuSamuel C Dudley

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