Hypertension. 2002;40:477-484
Published online before print August 26, 2002, doi: 10.1161/01.HYP.0000032031.30374.32
Published online before print August 26, 2002, doi: 10.1161/01.HYP.0000032031.30374.32
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(Hypertension. 2002;40:477.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure
From the Department of Cardiology, Guy’s King’s & St Thomas’ School of Medicine (Denmark Hill Campus), King’s College London, London, United Kingdom.
Correspondence to Ajay M Shah MD, FRCP, Department of Cardiology, GKT School of Medicine (Denmark Hill Campus), Bessemer Road, London SE5 9PJ, United Kingdom. E-mail ajay.shah{at}kcl.ac.uk
Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O2- production in LV homogenates, measured by lucigenin (5 µmol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by 
40% at the stage of LV decompensation; P<0.05). O2- production was fully inhibited by diphenyleneiodonium (100 µmol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22phox, gp91phox, p67phox, and p47phox in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O2- production, there was a significant increase in activation of extracellular signal–regulated kinase 1/2, extracellular signal–regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure.
Key Words: hypertrophy • free radicals • heart failure • myocardium • reactive oxygen species
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