Transglutaminase inhibitors attenuate vascular calcification in a preclinical model.
Transglutaminase inhibitors attenuate vascular calcification in a preclinical model.
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DOI：
10.1161/atvbaha.112.300260
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Nurminskaya MV
中科院分区：
文献类型：
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作者：
Beazley KE;Banyard D;Lima F;Deasey SC;Nurminsky DI;Konoplyannikov M;Nurminskaya MV
在体外，转氨酶2（TG 2）介导的β-连环蛋白信号通路的激活是华法林诱导的钙化的中心，这有助于探讨该信号轴作为体内血管钙化预防性治疗靶点的重要性。在大鼠模型中，华法林诱导的弹性蛋白钙沉着症的不良反应包括主动脉中膜钙化、血管壁细胞成分丢失和孤立性收缩期高血压，与TG 2的蓄积和激活以及β-连环蛋白信号传导的激活相关。华法林的这些作用可以通过腹腔内给予TG 2特异性抑制剂KCC-009或饮食补充已知抑制β-连环蛋白信号传导的双羟黄酮槲皮素而完全逆转。我们的研究还揭示了槲皮素抑制TG 2的能力。槲皮素逆转了华法林诱导的收缩压升高，这是该治疗的功能性结果。分子分析表明，槲皮素饮食稳定了平滑肌的表型，并阻止其转化为成骨细胞。TG 2/β-连环蛋白信号轴的抑制似乎可以预防华法林诱导的弹性钙化并控制单纯收缩期高血压。
In vitro, transglutaminase 2 (TG2)-mediated activation of the β-catenin signaling pathway is central in warfarin-induced calcification, warranting inquiry into the importance of this signaling axis as a target for preventive therapy of vascular calcification in vivo. The adverse effects of warfarin-induced elastocalcinosis in a rat model include calcification of the aortic media, loss of the cellular component in the vessel wall, and isolated systolic hypertension, associated with accumulation and activation of TG2 and activation of β-catenin signaling. These effects of warfarin can be completely reversed by intraperitoneal administration of the TG2-specific inhibitor KCC-009 or dietary supplementation with the bioflavonoid quercetin, known to inhibit β-catenin signaling. Our study also uncovers a previously uncharacterized ability of quercetin to inhibit TG2. Quercetin reversed the warfarin-induced increase in systolic pressure, underlying the functional consequence of this treatment. Molecular analysis shows that quercetin diet stabilizes the phenotype of smooth muscle and prevents its transformation into osteoblastic cells. Inhibition of the TG2/β-catenin signaling axis appears to prevent warfarin-induced elastocalcinosis and to control isolated systolic hypertension.