Transient Receptor Potential Channel Canonical Type 3 Deficiency Antagonizes Myofibroblast Transdifferentiation In Vivo

OBJECTIVE: Myofibroblast transformation has been shown to be associated with the reactive oxygen species- (ROS-) producing enzyme NADPH oxidase (Nox4). Inhibition of transient receptor potential channel canonical type 3 (TRPC3) attenuates mitochondrial calcium handling and ROS production in the vasculature of hypertensive rats. However, it remains elusive whether TRPC3 regulates mitochondrial calcium and ROS production and participates in myofibroblast transdifferentiation during wound healing. METHODS AND RESULTS: In this study, we demonstrated that activation of TRPC3 by transforming growth factor β (TGFβ (TGFαSMA). Inhibition of TRPC3 with its specific inhibitor, Pyr3, significantly decreased TGFβ (TGFαSMA). Inhibition of TRPC3 with its specific inhibitor, Pyr3, significantly decreased TGFβ (TGFβ (TGFTrpc3(−/−) mice exhibited significantly attenuated myofibroblast transdifferentiation, as demonstrated by decreased αSMA). Inhibition of TRPC3 with its specific inhibitor, Pyr3, significantly decreased TGFβ (TGFβ (TGFTrpc3(−/−) mice exhibited significantly attenuated myofibroblast transdifferentiation, as demonstrated by decreased Trpc3(+/+) mice. In addition, Trpc3(−/−) mice exhibited significantly attenuated myofibroblast transdifferentiation, as demonstrated by decreased CONCLUSIONS: Our data indicate that TGFβ1-mediated activation of TRPC3 enhances mitochondrial calcium and ROS production, which promotes myofibroblast transdifferentiation and HTS formation. Inhibition of the TRPC3-mediated Nox4/pSmad2/3 pathway may be a useful strategy to limit HTS formation after injury.β (TGF