Inhibition of c-Src Tyrosine Kinase Prevents Angiotensin II-Mediated Connexin43 Remodeling and Sudden Cardiac Death
| Autor: | Vibhash Kumar, Samuel C. Dudley, Kun Wang, Zhe Jiao, Ali A. Sovari, Heather S. Duffy, Kenneth E. Bernstein, Shahriar Iravanian, Marcelo G. Bonini, Elena Dolmatova, Hong Liu, Shadi Zandieh |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
medicine.medical_specialty
Blotting Western Connexin Mice Transgenic 030204 cardiovascular system & hematology Ventricular tachycardia Sudden death sudden cardiac death Article Sudden cardiac death CSK Tyrosine-Protein Kinase Mice 03 medical and health sciences 0302 clinical medicine Internal medicine c-Src tyrosine kinase Telemetry Medicine Animals Enzyme Inhibitors Phosphorylation 030304 developmental biology 0303 health sciences business.industry Angiotensin II Gap Junctions Protein-Tyrosine Kinases medicine.disease Immunohistochemistry 3. Good health connexin43 Blot Disease Models Animal Pyrimidines Endocrinology Death Sudden Cardiac src-Family Kinases Connexin 43 Ventricular Fibrillation Ventricular fibrillation Tachycardia Ventricular cardiovascular system Pyrazoles sense organs biological phenomena cell phenomena and immunity Cardiology and Cardiovascular Medicine business Tyrosine kinase |
| Popis: | ObjectivesThe 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).BackgroundRenin-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.MethodsWild-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.ResultsThe 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.ConclusionsRenin-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. |
| Databáze: | OpenAIRE |
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