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


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.


CONCLUSIONS
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.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 108 N Greene St, Baltimore, MD 21201, USA.
Kelly E
KE
Beazley
Stephanie
S
Deasey
Florence
F
Lima
Maria V
MV
Nurminskaya
D000818:Animals; D000925:Anticoagulants / Q000633:toxicity; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D061205:Vascular Calcification / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D014859:Warfarin / Q000633:toxicity*; D051176:beta Catenin / Q000378:metabolism*
D000925:Anticoagulants; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; C000717609:Tgm2 protein, rat; D051176:beta Catenin; D014859:Warfarin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins