Contractile Function During Angiotensin-II Activation

Fro Ph ne XII Bio of Bio Zh Lis Ma 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) Ca2þ uptake in transgenic mice, increased the Ca2þ 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 Nox2modulates cardiomyocyte SR Ca2þ 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. (J Am Coll Cardiol 2015;66:261–72) © 2015 by the American College of Cardiology Foundation. Published by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). P hysiological cardiac function requires precise regulation of intracellular calcium ions ([Ca]i) and excitation-contraction coupling. Aberrant cardiomyocyte Ca2þ handling contributes to contractile dysfunction, arrhythmia, hypertrophy, m the *King’s College London British Heart Foundation Centre of Exc ysiology, University of Pennsylvania Perelman School of Medicine, Phila ering and Technology, University of Maryland School of Medicine, Baltim , University of Bahia State, Guanambi, Brazil; and the kDepartment of Mol technology Center, University of Torino, Torino, Italy. This study was fund Excellence Award and the British Heart Foundation (RG/13/11/30384, R tech. All other authors have reported that they have no relationships rel ang and Prosser contributed equally to this work. ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Vale nuscript received May 4, 2015; accepted May 5, 2015. and cell death during heart failure (HF) (1). Reactive oxygen species (ROS) modulate cardiomyocyte [Ca]i fluxes through oxidation-reduction regulation of proteins involved in excitation-contraction coupling, both physiologically and in HF when ROS production ellence, London, United Kingdom; yDepartment of delphia, Pennsylvania; zCenter for Biomedical Engiore, Maryland; xDepartment of Education, Campus ecular Biotechnology and Health Sciences, Molecular ed by the Foundation Leducq Transatlantic Network E/13/2/30182). Dr. Hirsch is a cofounder of Kither evant to the contents of this paper to disclose. Drs.