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1 Induces Nox 4 NAD(P)H Oxidase and Reactive Oxygen Species-Dependent Proliferation in Human Pulmonary Artery Smooth Muscle Cells
1 Division of Respiratory, Critical Care and Occupational Pulmonary Medicine, University of Utah, Salt Lake City, UT, USA
2 Division of Cardiovascular Surgery, University of Utah, Salt Lake City, UT, USA
* To whom correspondence should be addressed. E-mail: Thomas.Kennedy{at}hsc.utah.edu.
Transforming growth factor 
1 (TGF1) is abundantly expressed in pulmonary hypertension, but its effect on the pulmonary circulation remain unsettled. We therefore studied TGF1 stimulation of freshly isolated human pulmonary artery smooth muscle cells (HPASMC). TGF1 initially (24 h) promoted differentiation, with up-regulated expression of smooth muscle contractile proteins. TGF1 also induced expression of Nox4, the only NAD(P)H oxidase homologue found in HPASMC, through Smad 2/3 signaling but not mitogen-activated protein (MAP)kinases. TGF1 likewise increased production of reactive oxygen species (ROS), an effect significantly reduced by the NAD(P)H oxidase inhibitor diphenylene iodonium (DPI) and by Nox4 siRNAs. In the absence of TGF1, Nox4 was initially present in freshly cultured cells but progressively lost with passage, paralleling a decrease in ROS production over time. At a later time point (72 h), TGF1 promoted HPASMC proliferation in a manner partially inhibited by Nox4 siRNA and dominant negative Smad 2/3, indicating that TGF1 produces HPASMC growth in part by a redox-dependent mechanism mediated through induction of Nox4. HPASMC activation of the MAP kinases ERK1/2 was reduced by the NAD(P)H oxidase inhibitors DPI and 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), suggesting that TGF1 may facilitate proliferation by up-regulating Nox4 and ROS production, with transient oxidative inactivation of phosphatases and augmentation of growth signaling cascades. These findings suggest that Nox4 is the relevant Nox homologue in HPASMC. This is the first observation that TGF1 regulates Nox4, with important implications for pulmonary arterial vascular remodeling in vivo.
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