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

ABSTRACT: 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.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.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.

SUBMITTER: Beazley KE

PROVIDER: S-EPMC3374407 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Beazley Kelly E KE Deasey Stephanie S Lima Florence F Nurminskaya Maria V MV

Arteriosclerosis, thrombosis, and vascular biology 20111027 1

<h4>Objective</h4>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.<h4>Methods and results</h4>Warfarin-induced calcification in rat A10 VSMCs is associated with the acti ...[more]

PMID: 22034513

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Project description:Vascular calcification (VC) is highly prevailing in cardiovascular disease, diabetes mellitus, and chronic kidney disease and, when present, is associated with cardiovascular events and mortality. The osteogenic differentiation of vascular smooth muscle cells (VSMCs) is regarded as the foundation for mediating VC. Related transcriptional enhancer factor (RTEF-1), also named as transcriptional enhanced associate domain (TEAD) 4 or transcriptional enhancer factor-3 (TEF-3), is a nuclear transcriptional factor with a potent effect on cardiovascular diseases, apart from its oncogenic role in the canonical Hippo pathway. However, the role and mechanism of RTEF-1 in VC, particularly in calcification of VSMCs, are poorly understood. Our results showed that RTEF-1 was reduced in calcified VSMCs. RTEF-1 significantly ameliorated β-glycerophosphate (β-GP)-induced VSMCs calcification, as detected by alizarin red staining and calcium content assay. Also, RTEF-1 reduced alkaline phosphatase (ALP) activity and decreased expressions of osteoblast markers such as Osteocalcin and Runt-related transcription factor-2 (Runx2), but increased expression of contractile protein, including SM α-actin (α-SMA). Additionally, RTEF-1 inhibited β-GP-activated Wnt/β-catenin pathway which plays a critical role in calcification and osteogenic differentiation of VSMCs. Specifically, RTEF-1 reduced the levels of Wnt3a, p-β-catenin (Ser675), glycogen synthase kinase-3β (GSK-3β), and p-GSK-3β (Ser9), but increased the levels of p-β-catenin (Ser33/37). Also, RTEF-1 increased the ratio of p-β-catenin (Ser33/37) to β-catenin proteins and decreased the ratio of p-GSK-3β (Ser9) to GSK-3β protein. LiCl, a Wnt/β-catenin signaling activator, was observed to reverse the protective effect of RTEF-1 overexpression on VSMCs calcification induced by β-GP. Accordingly, Dickkopf-1 (Dkk1), a Wnt antagonist, attenuated the role of RTEF-1 deficiency in β-GP-induced VSMCs calcification. Taken together, we concluded that RTEF-1 ameliorated β-GP-induced calcification and osteoblastic differentiation of VSMCs by inhibiting Wnt/β-catenin signaling pathway.

Dataset Information

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

Publications

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

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