Transglutaminase 2–Mediated Activation of β-Catenin Signaling Has a Critical Role in Warfarin-Induced Vascular Calcification
| Autor: | Kelly E. Beazley, Stephanie Deasey, Maria Nurminskaya, Florence Lima |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Vascular smooth muscle Beta-catenin Myocytes Smooth Muscle Biology Article Cell Line Mice Downregulation and upregulation GTP-Binding Proteins Internal medicine medicine Animals Protein Glutamine gamma Glutamyltransferase 2 Vascular Calcification beta Catenin Mice Knockout Transglutaminases Transdifferentiation Models Cardiovascular Wnt signaling pathway Anticoagulants medicine.disease Rats Up-Regulation Cell biology Mice Inbred C57BL Endocrinology DKK1 biology.protein Warfarin Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction Calcification |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 32:123-130 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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