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Inhibition of Renin-Angiotensin System (RAS) Reduces Ventricular Tachycardia Risk by Altering Connexin43

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Title: Inhibition of Renin-Angiotensin System (RAS) Reduces Ventricular Tachycardia Risk by Altering Connexin43
Author(s): Iravanian, Shahriar; Sovari, Ali A.; Lardin, Harvey A.; Liu, Hong; Xiao, Hong D.; Dolmatova, Elena; Jiao, Zhe; Harris, Brett S.; Witham, Emily A.; Gourdie, Robert G.; Duffy, Heather S.; Bernstein, Kenneth E.; Dudley Jr., Samuel C.
Abstract: Aims: Renin-angiotensin system (RAS) activation is associated with arrhythmias. We investigated the effects of RAS inhibition in cardiac-specific angiotensin converting enzyme (ACE) overexpression (ACE 8/8) mice, which exhibit proclivity to ventricular tachycardia (VT) and sudden death because of reduced connexin43 (Cx43). Methods and Results: ACE 8/8 mice were treated with an ACE inhibitor (captopril) or an angiotensin receptor type-1 blocker (losartan). Subsequently, electrophysiological studies were performed, and the hearts were extracted for Cx43 quantification using immunoblotting, immunohistochemistry, fluorescent dye spread method and sodium current quantification using whole cell patch clamping. VT was induced in 12.5% of captopril treated ACE 8/8 and in 28.6% of losartan treated mice, compared to 87.5% of untreated mice (P<0.01). Losartan and captopril treatment increased total Cx43 2.4-fold (P=0.01) and the Cx43 phosphorylation ratio 2.3-fold (P=0.005). Treatment was associated with a recovery of gap junctional conductance. Survival in treated mice improved to 0.78 at 10 weeks (95% confidence interval 0.64 to 0.92), compared to the expected survival of less than 0.50. Conclusions: In a model of RAS activation, arrhythmic risk was correlated with reduced Cx43 amount and phosphorylation. RAS inhibition resulted in increased total and phosphorylated Cx43, decreased VT inducibility, and improved survival.
Issue Date: 2011-07
Publisher: Springer Verlag
Citation Info: Iravanian, S., Sovari, A. A., Lardin, H. A., Liu, H., Xiao, H. D., Dolmatova, E., Jiao, Z., Harris, B. S., Witham, E. A., Gourdie, R. G., Duffy, H. S., Bernstein, K. E., & Dudley, J. 2011. Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43. Journal of Molecular Medicine, 89(7): 677-687. DOI: 10.1007/s00109-011-0761-3
Type: Article
Description: Post print version of article may differ from published version. The original publication is available at springerlink.com; DOI: 10.1007/s00109-011-0761-3.
URI: http://hdl.handle.net/10027/8244
ISSN: 0946-2716
Date Available in INDIGO: 2012-03-21
 

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