title: c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction.
abstract: OBJECTIVE
  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.affiliation: Department 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.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Rutledge
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
authors.forename: Fu Siong
authors.initials: FS
authors.lastname: Ng
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sulkin
authors.affiliation: Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Greener
authors.affiliation: Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island.
authors.forename: Artem M
authors.initials: AM
authors.lastname: Sergeyenko
authors.affiliation: Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gemel
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Illinois.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Beyer
authors.affiliation: Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.affiliation: Department of Biomedical Engineering, Washington University, St. Louis, Missouri.
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
authors.affiliation: Lifespan Cardiovascular Institute, the Warren Alpert School of Medicine of Brown University, and the Providence Veterans Administration Medical Center, Providence. Rhode Island. Electronic address: samuel_dudley@brown.edu.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism* / Q000503:physiopathology; D052117:Benzodioxoles / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D018031:Connexin 43 / Q000378:metabolism*; D003645:Death, Sudden; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D052117:Benzodioxoles; D018031:Connexin 43; D004791:Enzyme Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; C515233:saracatinib; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D054645:Protein Phosphatase 1
keywords: Src; connexin43; gap junctions; myocardial infarction; sudden death