Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43

Shahriar Iravanian, Ali A. Sovari, Harvey A. Lardin, Hong Liu, Hong D. Xiao, Elena Dolmatova, Zhe Jiao, Brett S. Harris, Emily A. Witham, Robert G. Gourdie, Heather S. Duffy, Kenneth E. Bernstein, Samuel C. Dudley

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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). 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. 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.

Original languageEnglish (US)
Pages (from-to)677-687
Number of pages11
JournalJournal of Molecular Medicine
Volume89
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • ACE
  • Angiotensin
  • Arrhythmia
  • Connexin
  • Electrophysiology

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