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Basic Science| Volume 62, ISSUE 6, P861-872, June 2013

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Renin Inhibition and AT1R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling

  • Adam Whaley-Connell
    Correspondence
    Corresponding author. Harry S Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65211, USA. Tel.: +1 573 882 2273; fax:+1 573 884 5530.
    Affiliations
    Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA

    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Division of Nephrology and Hypertension, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
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  • Javad Habibi
    Affiliations
    Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA

    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
    Search for articles by this author
  • Nathan Rehmer
    Affiliations
    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA
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  • Sivakumar Ardhanari
    Affiliations
    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA
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  • Melvin R. Hayden
    Affiliations
    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
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  • Lakshmi Pulakat
    Affiliations
    Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA

    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Department of Nutrition and Exercise Physiology, 217 Gwynn Hall, Columbia, MO 65211, USA

    Division of Nephrology and Hypertension, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
    Search for articles by this author
  • Caroline Krueger
    Affiliations
    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA
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  • Carlos M. Ferrario
    Affiliations
    Departments of Surgery, Internal Medicine-Nephrology, and Physiology-Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1090, USA
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  • Vincent G. DeMarco
    Affiliations
    Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA

    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Department of Medical Pharmacology and Physiology, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Division of Cardiovascular Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
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  • James R. Sowers
    Affiliations
    Research Service, Harry S. Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA

    University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA

    Department of Internal Medicine, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Department of Medical Pharmacology and Physiology, MA415 Medical Sciences Building, One Hospital Drive, Columbia, MO 65212, USA

    Divisionof Endocrinology, Diabetes and Metabolism, One Hospital Drive, Columbia, MO 65212, USA

    Diabetes and Cardiovascular Center, One Hospital Drive, Columbia, MO 65212, USA
    Search for articles by this author
Published:January 28, 2013DOI:https://doi.org/10.1016/j.metabol.2012.12.012

      Abstract

      Objective

      Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone.

      Materials/Methods

      We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin–angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days.

      Results

      Compared to Sprague–Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone.

      Conclusions

      Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression.

      Abbreviations:

      Angt II (angiotensin II), ACE (angiotensin-converting enzyme), AT1R (Ang II type 1 receptor), EF (ejection fraction), FS (fractional shortening), HPA (heme-pomatia agglutinin), LV (left ventricular), LVID (LV internal diameter), mTOR (mammalian target of rapamycin), MR (mineralocorticoid receptor), GalNAc (N-acetylgalactosamine), PWT (posterior wall thicknesses), ROS (reactive oxygen species), RWT (relative wall thickness), RAS (renin–angiotensin system), RAAS (renin–angiotensin–aldosterone system), SWT (septal wall thicknesses), SD (Sprague–Dawley), SBP (systolic blood pressure), 3-NT (3-nitrotyrosine), Ren2 (transgenic TG(mRen2)27 rat), VVG (Verhoeff van Gieson)

      Keywords

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