The synthesis of extracellular matrix including collagen during wound healing responses involves signaling via reactive oxygen species (ROS). We hypothesized that NADPH oxidase isoform Nox4 facilitates the stimulatory effects of the profibrotic cytokine transforming growth factor (TGF) β₁ on collagen production in vitro and in vivo. TGFβ₁ stimulated collagen synthesis and hydrogen peroxide generation in mouse cardiac fibroblasts, and both responses were attenuated by a scavenger of superoxide and hydrogen peroxide (EUK-134). Furthermore, by expressing a dominant negative form of Nox4 (Adv-Nox4^ΔNADPH) in fibroblasts, TGFβ₁-induced hydrogen peroxide production and collagen production were abrogated, suggesting that Nox4-dependent ROS are important for TGFβ₁ signaling in collagen production. This was confirmed by the inhibitory effect of an adenovirus carrying siRNA targeting Nox4 (Adv-Nox4i) on TGFβ₁-induced collagen synthesis and expression of activated myofibroblasts marker smooth muscle alpha actin. Finally we used a mouse model of subcutaneous sponge implant to examine the role of Nox4 in the local stimulatory effects of TGFβ₁ on collagen accumulation in vivo. TGFβ₁-induced collagen accumulation was significantly reduced when the sponges were instilled with Adv-Nox4^ΔNADPH. In conclusion, Nox4 acts as an intermediary in the signaling of TGFβ₁ to facilitate collagen synthesis.

Item Type:	Refereed Article
Keywords:	TGFb, Nox4, collagen, fibroblasts, sponge implant
Research Division:	Biomedical and Clinical Sciences
Research Group:	Medical biotechnology
Research Field:	Gene and molecular therapy
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Liu, GS (Associate Professor Guei-Sheung Liu)
ID Code:	120807
Year Published:	2013
Web of Science® Times Cited:	56
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2017-08-30
Last Modified:	2017-11-03
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