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

作者：Al Ghouleh Imad; Frazziano Giovanna; Rodriguez Andres I; Csanyi Gabor; Maniar Salony; St Croix Claudette M; Kelley Eric E; Egana Loreto A; Song Gyun Jee; Bisello Alessandro; Lee Yong J; Pagano Patrick J^*

来源：Cardiovascular Research, 2013, 97(1): 134-142.

DOI：10.1093/cvr/cvs295

• NADPH oxidase
• Hydrogen peroxide
• Aquaporin
• Ask1
• 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 (H2O2) in vascular disease, and plasma H2O2 levels in the micromolar range are detectable in animal models and humans with hypertension. Recently, H2O2 was shown to cross biological membranes of non-vascular cells via aquaporin (Aqp) water channels. Previous findings suggest that H2O2 activates NADPH oxidase (Nox) enzymes in vascular cells and apoptosis signal-regulating kinase 1 (Ask1) in non-vascular cells. We hypothesized that extracellular H2O2 induces smooth muscle cell (SMC) hypertrophy by a mechanism involving Aqp1, Nox1, and Ask1.
Treatment of rat aortic SMCs (rASMC) with exogenous H2O2 resulted in a concentration-dependent increase in Nox-derived superoxide (O-2(center dot)), 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 H2O2 cellular entry and H2O2-induced O-2(center dot) production. H2O2 treatment increased Ask1 activation and induced rASMC hypertrophy in a Nox1-dependent mechanism. Adenoviral-dominant-negative Ask1 attenuated H2O2-induced rASMC hypertrophy and adenoviral overexpression of Ask1 augmented it.
Our results demonstrate for the first time that extracellular H2O2, at pathophysiological concentrations, stimulates rASMC Nox1-derived O-2(center dot), subsequent Ask1 activation and SMC hypertrophy. The data demonstrate a novel pathway by which H2O2 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.

• 出版日期2013-1-1