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Contractile Function During Angiotensin-II Activation

Zhang, Min et al.

Journal of the American College of Cardiology. Volume 66:Issue 3 (2015); pp 261-272 -- Elsevier Science

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  • Title:
    Contractile Function During Angiotensin-II Activation
  • Author: Zhang, Min;
    Prosser, Benjamin L.;
    Bamboye, Moradeke A.;
    Gondim, Antonio N.S.;
    Santos, Celio X.;
    Martin, Daniel;
    Ghigo, Alessandra;
    Perino, Alessia;
    Brewer, Alison C.;
    Ward, Christopher W.;
    Hirsch, Emilio;
    Lederer, W. Jonathan;
    Shah, Ajay M.
  • Found In: Journal of the American College of Cardiology. Volume 66:Issue 3 (2015); pp 261-272
  • Journal Title: Journal of the American College of Cardiology
  • Subjects: Cardiology--Periodicals; Cardiology--Research; Medicine--Periodicals; Ang II--[Ca2+]i--HF--LV--NADPH--NCX--Nox2--PKA--PP1--RAS--ROS--RyR2--SERCA--SR; angiotensin II--contraction--myocyte--NADPH oxidase; Dewey: 616.12
  • Rights: Licensed
  • Publication Details: Elsevier Science
  • Abstract: Abstract Background Renin-angiotensin system activation is a feature of many cardiovascular conditions. Activity of myocardial reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NADPH oxidase 2 or Nox2) is enhanced by angiotensin II (Ang II) and contributes to increased hypertrophy, fibrosis, and adverse remodeling. Recent studies found that Nox2-mediated reactive oxygen species production modulates physiological cardiomyocyte function. Objectives This study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation. Methods We generated a cardiomyocyte-targeted Nox2-transgenic mouse model and studied the effects of in vivo and ex vivo Ang II stimulation, as well as chronic aortic banding. Results Chronic subpressor Ang II infusion induced greater cardiac hypertrophy in transgenic than wild-type mice but unexpectedly enhanced contractile function. Acute Ang II treatment also enhanced contractile function in transgenic hearts in vivo and transgenic cardiomyocytes ex vivo. Ang II–stimulated Nox2 activity increased sarcoplasmic reticulum (SR) Ca 2+ uptake in transgenic mice, increased the Ca 2+ transient and contractile amplitude, and accelerated cardiomyocyte contraction and relaxation. Elevated Nox2 activity increased phospholamban phosphorylation in both hearts and cardiomyocytes, related to inhibition of protein phosphatase 1 activity. In a model of aortic banding–induced chronic pressure overload, heart function was similarly depressed in transgenic and wild-type mice. Conclusions We identified a novel mechanism in which Nox2 modulates cardiomyocyte SR Ca 2+ uptake and contractile function through redox-regulated changes in phospholamban phosphorylation. This mechanism can drive increased contractility in the short term in disease states characterized by enhanced renin-angiotensin system activation.
  • Identifier: System Number: ETOCvdc_100065267393.0x000001; Journal ISSN: 0735-1097; 10.1016/j.jacc.2015.05.020
  • Publication Date: 2015
  • Physical Description: Electronic
  • Shelfmark(s): 4685.500000
  • UIN: ETOCvdc_100065267393.0x000001

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