Transglutaminase 2-mediated activation of β-catenin signaling has a critical role in warfarin-induced vascular calcification

Kelly E. Beazley, Stephanie Deasey, Florence Lima, Maria V. Nurminskaya

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


Objective-: Accumulating experimental evidence implicates β-catenin signaling and enzyme transglutaminase 2 (TG2) in the progression of vascular calcification, and our previous studies have shown that TG2 can activate β-catenin signaling in vascular smooth muscle cells (VSMCs). Here we investigated the role of the TG2/β-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 β-catenin signaling and is independent of oxidative stress. The canonical β-catenin inhibitor Dkk1, but not the Wnt antagonist Wif-1, prevents warfarin-induced activation of β-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 β-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 β-catenin signaling in VSMCs. Inhibition of canonical β-catenin pathway or TG2 activity prevents warfarin-regulated calcification, identifying the TG2/β-catenin axis as a novel therapeutic target in vascular calcification.

Original languageEnglish
Pages (from-to)123-130
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number1
StatePublished - Jan 2012


  • calcification
  • transglutaminase 2
  • vascular biology
  • warfarin
  • β-catenin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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