Activation of NADPH oxidase during progression of cardiac hypertrophy to failure.
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 micro mol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by approximately 40% at the stage of LV decompensation; P<0.05). O2- production was fully inhibited by diphenyleneiodonium (100 micromol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22(phox), gp91(phox), p67(phox), and p47(phox) 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.
D000818:Animals; D018450:Disease Progression; D004789:Enzyme Activation; D006168:Guinea Pigs; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000209:etiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits; D017382:Reactive Oxygen Species / Q000378:metabolism
D021122:Protein Subunits; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases