TY - JOUR
T1 - Inhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac death
AU - Sovari, Ali A.
AU - Iravanian, Shahriar
AU - Dolmatova, Elena
AU - Jiao, Zhe
AU - Liu, Hong
AU - Zandieh, Shadi
AU - Kumar, Vibhash
AU - Wang, Kun
AU - Bernstein, Kenneth E.
AU - Bonini, Marcelo G.
AU - Duffy, Heather S.
AU - Dudley, Samuel C.
PY - 2011/11/22
Y1 - 2011/11/22
N2 - Objectives: 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 systeminduced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity.
AB - Objectives: 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 systeminduced arrhythmias and that c-Src inhibitors might exert antiarrhythmic activity.
KW - angiotensin II
KW - c-Src tyrosine kinase
KW - connexin43
KW - sudden cardiac death
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U2 - 10.1016/j.jacc.2011.07.048
DO - 10.1016/j.jacc.2011.07.048
M3 - Article
C2 - 22093512
AN - SCOPUS:81255163198
SN - 0735-1097
VL - 58
SP - 2332
EP - 2339
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 22
ER -