Aquaporin 1, Nox1, and Ask1 mediate oxidant-induced smooth muscle cell hypertrophy

Reactive oxygen species (ROS)-mediated intracellular signalling is well described in the vasculature, yet the precise roles of ROS in paracrine signalling are not known. Studies implicate interstitial ROS hydrogen peroxide (H(2)O(2)) in vascular disease, and plasma H(2)O(2) levels in the micromolar...

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Published in:Cardiovascular research 2013-01, Vol.97 (1), p.134-142
Main Authors: Al Ghouleh, Imad, Frazziano, Giovanna, Rodriguez, Andres I, Csányi, Gábor, Maniar, Salony, St Croix, Claudette M, Kelley, Eric E, Egaña, Loreto A, Song, Gyun Jee, Bisello, Alessandro, Lee, Yong J, Pagano, Patrick J
Format: Article
Language:English
Subjects:
Animals
Aquaporin 1 - genetics
Aquaporin 1 - metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Electron Spin Resonance Spectroscopy
Enzyme Activation
Flow Cytometry
Hydrogen Peroxide - pharmacology
Hypertrophy
MAP Kinase Kinase Kinase 5 - genetics
MAP Kinase Kinase Kinase 5 - metabolism
Microscopy, Confocal
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - enzymology
Muscle, Smooth, Vascular - pathology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - enzymology
Myocytes, Smooth Muscle - pathology
NADH, NADPH Oxidoreductases - metabolism
NADPH Oxidase 1
Original
Oxidants - pharmacology
Phosphorylation
Rats
RNA Interference
Signal Transduction - drug effects
Superoxides - metabolism
Time Factors
Transfection
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Summary:Reactive oxygen species (ROS)-mediated intracellular signalling is well described in the vasculature, yet the precise roles of ROS in paracrine signalling are not known. Studies implicate interstitial ROS hydrogen peroxide (H(2)O(2)) in vascular disease, and plasma H(2)O(2) levels in the micromolar range are detectable in animal models and humans with hypertension. Recently, H(2)O(2) was shown to cross biological membranes of non-vascular cells via aquaporin (Aqp) water channels. Previous findings suggest that H(2)O(2) activates NADPH oxidase (Nox) enzymes in vascular cells and apoptosis signal-regulating kinase 1 (Ask1) in non-vascular cells. We hypothesized that extracellular H(2)O(2) induces smooth muscle cell (SMC) hypertrophy by a mechanism involving Aqp1, Nox1, and Ask1. Treatment of rat aortic SMCs (rASMC) with exogenous H(2)O(2) resulted in a concentration-dependent increase in Nox-derived superoxide (O(2)(•-)), determined by L-012 chemiluminescence, cytochrome c and electron paramagnetic resonance. Nox1 was verified as the source of O(2)(·-) by siRNA. Aqp1 siRNA attenuated H(2)O(2) cellular entry and H(2)O(2)-induced O(2)(•-) production. H(2)O(2) treatment increased Ask1 activation and induced rASMC hypertrophy in a Nox1-dependent mechanism. Adenoviral-dominant-negative Ask1 attenuated H(2)O(2)-induced rASMC hypertrophy and adenoviral overexpression of Ask1 augmented it. Our results demonstrate for the first time that extracellular H(2)O(2), at pathophysiological concentrations, stimulates rASMC Nox1-derived O(2)(•-), subsequent Ask1 activation and SMC hypertrophy. The data demonstrate a novel pathway by which H(2)O(2) enters vascular cells via aquaporins and activates Nox, leading to hypertrophy, and provide multiple novel targets for combinatorial therapeutics development targeting hypertrophy and vascular disease.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvs295