Transglutaminase 2–Mediated Activation of -Catenin Signaling Has a Critical Role in Warfarin-Induced

Objective—Accumulating experimental evidence implicates -catenin signaling and enzyme transglutaminase 2 (TG2) in the progression of vascular calcification, and our previous studies have shown that TG2 can activate -catenin signaling in vascular smooth muscle cells (VSMCs). Here we investigated the role of the TG2/-catenin signaling axis in vascular calcification induced by warfarin. Methods and Results—Warfarin-induced calcification in rat A10 VSMCs is associated with the activation of -catenin signaling and is independent of oxidative stress. The canonical -catenin inhibitor Dkk1, but not the Wnt antagonist Wif-1, prevents warfarin-induced activation of -catenin, calcification, and osteogenic transdifferentiation in VSMCs. TG2 expression and activity are increased in warfarin-treated cells, in contrast to canonical Wnt ligands. Vascular cells with genetically or pharmacologically reduced TG2 activity fail to activate -catenin in response to warfarin. Moreover, warfarin-induced calcification is significantly reduced on the background of attenuated TG2 both in vitro and in vivo. Conclusion—TG2 is a critical mediator of warfarin-induced vascular calcification that acts through the activation of -catenin signaling in VSMCs. Inhibition of canonical -catenin pathway or TG2 activity prevents warfarin-regulated calcification, identifying the TG2/-catenin axis as a novel therapeutic target in vascular calcification. (Arterioscler Thromb Vasc Biol. 2012;32:123-130.) Key Words: calcification vascular biology -catenin transglutaminase 2 warfari