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Increased myocardial NADPH oxidase activity in human heart failure

Christophe Heymes, PhD^*, Jennifer K. Bendall, MSc^*, Philippe Ratajczak, Alison C. Cave, PhD^*, Jane-Lise Samuel, MD, PhD, Gerd Hasenfuss, MD and Ajay M. Shah, MD, FRCP, FAHA^*,*

^* Department of Cardiology, Guy’s King’s and St. Thomas’s School of Medicine, King’s College London, United Kingdom
INSERM U572, IFR Circulation, Hôpital Lariboisiere, Paris, France
Department of Cardiology, University of Göttingen, Germany

View larger version (29K): [in a new window]   Figure 1 Myocardial nicotinamide adenine dinucleotide 3-phosphate (reduced form) (NADPH) oxidase expression and activity in nonfailing and end-stage failing human heart. (A) NADPH-dependent superoxide production in left ventricular homogenates measured by lucigenin-enhanced chemiluminescence. *p < 0.01 between groups. (B) Effect of specific inhibitors (Inhib) of enzymatic reactive oxygen species (ROS) production or of the superoxide scavenger Tiron. p < 0.001 for ROS production with and without inhibitor. (C) Representative immunoblots for NADPH oxidase subunits and for cardiac troponin I (cTnI). (D) Densitometric quantification of NADPH oxidase subunit expression relative to troponin I. DCM = dilated cardiomyopathy; DPI = diphenyleneiodonium; NYHA = New York Heart Association; L-NAME = N-nitro-L-arginine methyl ester.

View larger version (103K): [in a new window]   Figure 2 Representative immunofluorescence micrographs of human heart sections labeled for the nicotinamide adenine dinucleotide 3-phosphate (reduced form) oxidase subunit gp91phox. Panels a, c, e, and g show nonfailing heart tissue and panels b, d, f, and h show end-stage failing tissue. Transverse (a, b) and longitudinal (c, d) sections labeled for gp91phox show increased labeling in end-stage heart failure. Labeling for alpha-actinin (e, f) shows a typical intracellular pattern of myocyte costamer and intercalated disc labeling. Panels g and h show suprerposition of gp91phox and alpha-actinin labeling. All scale bars = 20 µm.

View larger version (127K): [in a new window]   Figure 3 Representative immunofluorescence micrographs of human heart sections labeled for the nicotinamide adenine dinucleotide 3-phosphate (reduced form) oxidase subunit p47phox. (A) Dual labeling for p47phox and alpha-actinin in nonfailing (a–c) and end-stage failing tissue (b–f). Panels a and d show labeling for p47phox; panels b and e show labeling for alpha-actinin; panels c and f show superimposed images. p47phox was detected in cardiac myocytes in both failing and nonfailing myocardium, with increased sarcolemmal labeling in the failing group (d and f vs. a and c). All scale bars = 20 µm. (B) Dual labeling for p47phox and vinculin, as a sarcolemmal marker, in nonfailing (a–c) and end-stage failing tissue (b–f). Panels a and d show labeling for p47phox; panels b and e show labeling for vinculin. Superposition of the p47phox and vinculin images (panels c and f) demonstrates the sarcolemmal localization of p47phox in the end-stage heart tissue (panel f, yellow color). All scale bars = 20 µm.