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

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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.

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Funding

This work was supported by National Institute of Health grants R01 HL085558 (SCD, KEB), R01 HL073753 (SCD), P01 HL058000 (SCD), DK039777 (KEB), American Heart Association (AHA) National Scientist Development Grant (HDX), and AHA postdoctoral fellowship (SI).

Conflicts of interest

The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Division of Cardiology, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, GA, 30033, USA

    Shahriar Iravanian & Zhe Jiao

  2. Division of Cardiology, University of Illinois at Chicago, 840 S. Wood Street, M/C 715, Chicago, IL, 60612, USA

    Ali A. Sovari, Harvey A. Lardin, Hong Liu & Samuel C. Dudley Jr.

  3. Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Hong D. Xiao

  4. Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA

    Elena Dolmatova & Heather S. Duffy

  5. Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC, 29425, USA

    Brett S. Harris & Robert G. Gourdie

  6. Biomedical Sciences Graduate Program, University of California, La Jolla, San Diego, CA, 92093, USA

    Emily A. Witham

  7. Departments of Pathology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Kenneth E. Bernstein

Authors
  1. Shahriar Iravanian
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  2. Ali A. Sovari
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  4. Hong Liu
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  7. Zhe Jiao
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  8. Brett S. Harris
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  13. Samuel C. Dudley Jr.
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Correspondence to Samuel C. Dudley Jr..

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Iravanian, S., Sovari, A.A., Lardin, H.A. et al. Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43. J Mol Med 89, 677–687 (2011). https://doi.org/10.1007/s00109-011-0761-3

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  • DOI: https://doi.org/10.1007/s00109-011-0761-3

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