title: Inhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac death.
abstract: OBJECTIVE
  The aim of this study was to test whether c-Src tyrosine kinase mediates connexin-43 (Cx43) reduction and sudden cardiac death in a transgenic mouse model of cardiac-restricted overexpression of angiotensin-converting enzyme (ACE8/8 mice).
  
  
  BACKGROUND
  Renin-angiotensin system activation is associated with an increased risk for arrhythmia and sudden cardiac death, but the mechanism is not well understood. The up-regulation of c-Src by angiotensin II may result in the reduction of Cx43, which impairs gap junction function and provides a substrate for arrhythmia.
  
  
  METHODS
  Wild-type and ACE8/8 mice with and without treatment with the c-Src inhibitor 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (PP1) were studied. Telemetry monitoring, in vivo electrophysiologic studies, Western blot analyses for total and phosphorylated c-Src and Cx43, immunohistochemistry staining for Cx43, and functional assessment of Cx43 with fluorescent dye diffusion were performed.
  
  
  RESULTS
  The majority of the arrhythmic deaths resulted from ventricular tachycardia degenerating to ventricular fibrillation (83%). Levels of total and phosphorylated c-Src were increased and Cx43 reduced in ACE8/8 mice. PP1 reduced total and phosphorylated c-Src levels, increased Cx43 level by 2.1-fold (p < 0.005), increased Cx43 at the gap junctions (immunostaining), improved gap junctional communication (dye spread), and reduced ventricular tachycardia inducibility and sudden cardiac death. The survival rate increased from 11% to 86% with 4 weeks of PP1 treatment (p < 0.005). Treatment with an inactive analog did not change survival or Cx43 levels.
  
  
  CONCLUSIONS
  Renin-angiotensin system activation is associated with c-Src up-regulation, Cx43 loss, reduced myocyte coupling, and arrhythmic sudden death, which can be prevented by c-Src inhibition. This suggests that an increase in c-Src activity may help mediate renin-angiotensin system-induced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity.
authors.affiliation: Section of Cardiology and Center for Cardiovascular Research, University of Illinois at Chicago, 840 S.Wood Street, Chicago, IL 60612, USA. scdudley@uic.edu
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Shahriar
authors.initials: S
authors.lastname: Iravanian
authors.forename: Elena
authors.initials: E
authors.lastname: Dolmatova
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jiao
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Shadi
authors.initials: S
authors.lastname: Zandieh
authors.forename: Vibhash
authors.initials: V
authors.lastname: Kumar
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Bernstein
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Bonini
authors.forename: Heather S
authors.initials: HS
authors.lastname: Duffy
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Dudley
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D018031:Connexin 43 / Q000378:metabolism*; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000378:metabolism / Q000517:prevention & control; D013686:Telemetry; D014693:Ventricular Fibrillation / Q000378:metabolism / Q000517:prevention & control; D019061:src-Family Kinases
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D018031:Connexin 43; D004791:Enzyme Inhibitors; C543076:GJA1 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases
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