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Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2015 Jul 21; Vol. 66 (3), pp. 261-272. - Publication Year :
- 2015
-
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.<br />Objectives: This study sought to investigate the effects of cardiomyocyte Nox2 on contractile function during increased Ang II activation.<br />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.<br />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.<br />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.<br /> (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Disease Models, Animal
Mice
Mice, Transgenic
Models, Cardiovascular
NADPH Oxidase 2
Phosphorylation physiology
Reactive Oxygen Species metabolism
Renin-Angiotensin System physiology
Sarcoplasmic Reticulum metabolism
Angiotensin II metabolism
Calcium metabolism
Calcium-Binding Proteins metabolism
Cardiovascular Diseases metabolism
Membrane Glycoproteins metabolism
Myocardial Contraction physiology
Myocytes, Cardiac metabolism
NADPH Oxidases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 66
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 26184620
- Full Text :
- https://doi.org/10.1016/j.jacc.2015.05.020