Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 282, Issue 4, Pages C926-C934Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00254.2001
Keywords
myocardial hypertrophy; norepinephrine; mitogen/extracellular signal-regulated kinase 1/2-extracellular signal-regulated kinase 1/2; Ras; NAP(P) H oxidase expression
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We recently reported that alpha(1)-adrenoceptor (alpha(1)-AR) stimulation induces hypertrophy via activation of the mitogen/extracellular signal-regulated kinase (MEK)1/2-extracellular signal-regulated kinase (ERK) 1/2 pathway and generates reactive oxygen species (ROS) in adult rat ventricular myocytes (ARVM). Here we investigate the intracellular source of ROS in ARVM and the mechanism by which ROS activate hypertrophic signaling after alpha(1)-AR stimulation. Pretreatment of ARVM with the ROS scavenger Mn(III) terakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) completely inhibited the alpha(1)-AR-stimulated activation of Ras-MEK1/2-ERK1/2. Direct addition of H2O2 or the superoxide generator menadione activated ERK1/2, which is also prevented by MnTMPyP pretreatment. We found that ARVM express gp91(phox), p22(phox), p67(phox), and p47(phox), four major components of NAD(P) H oxidase, and that alpha(1)-AR-stimulated ERK1/2 activation was blocked by four structurally unrelated inhibitors of NAD( P) H oxidase [diphenyleneiodonium, phenylarsine oxide, 4-(2-aminoethyl) benzenesulfonyl fluoride, and cadmium]. Conversely, inhibitors for other potential ROS-producing systems, including mitochondrial electron transport chain, nitric oxide synthase, xanthine oxidase, and cyclooxygenase, had no effect on alpha(1)-AR-stimulated ERK1/2 activation. Taken together, our results show that ventricular myocytes express components of an NAD( P) H oxidase that appear to be involved in alpha(1)-AR-stimulated hypertrophic signaling via ROS-mediated activation of Ras-MEK1/2-ERK1/2.
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