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  • Title: Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation.
    Author: Zhang M, Prosser BL, Bamboye MA, Gondim ANS, Santos CX, Martin D, Ghigo A, Perino A, Brewer AC, Ward CW, Hirsch E, Lederer WJ, Shah AM.
    Journal: J Am Coll Cardiol; 2015 Jul 21; 66(3):261-272. PubMed ID: 26184620.
    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.
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