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首页> 外文期刊>Translational research: the journal of laboratory and clinical medicine >Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy.
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Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy.

机译:动脉钙化:肿瘤坏死因子-α介导的血管Wnt病。

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Arterial calcification is common in patients with type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and other chronic inflammatory disorders. Arterial calcification is associated with significant morbidity and increased early mortality. The molecular signature of vascular calcification in diabetes is strikingly similar to that of CKD. Low-grade arterial inflammation is common to both conditions, and increased levels of tumor necrosis factor-alpha (TNF-alpha) have been reported in both DM and CKD. Recently, we described a novel TNF-alpha regulated Msx2-Wnt osteogenic program that regulates arterial calcification in an animal model of type 2 DM. TNF-alpha induces the osteogenic bone morphogenetic protein-2 (BMP-2), Msx2, Wnt3a, and Wnt7a mRNAs and leads to increased aortic calcium accumulation. Treatment with the TNF-alpha neutralizing antibody infliximab abrogates aortic BMP-2-Msx2-Wnt3a and Wnt7a signaling and attenuates aortic calcium accumulation significantly. Mice with vascular TNF-alphaaugmented by the SM22-TNF-alpha transgene upregulate the aortic Msx2-Wnt3a/Wnt7a axis. Furthermore, SM22-TNF-alphaTg;TOPGAL mice exhibit greater beta-galactosidase reporter staining versus TOPGAL siblings in the aorta and coronaries, which indicates enhanced mural Wnt signaling in response to TNF-alpha. Thus, inflammatory TNF-alpha signals promote aortic osteogenic Msx2-Wnt programs in type 2 DM, and arterial calcification in this model is a TNF-alpha-driven Wnt-opathy. Having established the role of TNF-alpha in diabetic vascular calcification, an unmet need exists to evaluate the role of TNF-alpha and Msx2-Wnt signals in CKD-related calcification models. If validated in these models, then these findings will have significant therapeutic applications.
机译:患有2型糖尿病(DM),慢性肾脏病(CKD)和其他慢性炎症性疾病的患者常见动脉钙化。动脉钙化与发病率高和早期死亡率增加有关。糖尿病中血管钙化的分子标记与CKD非常相似。低度动脉炎症在这两种情况下都很常见,并且在DM和CKD中都报告了肿瘤坏死因子-α(TNF-alpha)水平升高。最近,我们描述了一种新型的TNF-α调节的Msx2-Wnt成骨程序,该程序在2型DM动物模型中调节动脉钙化。 TNF-α诱导成骨性骨形态发生蛋白2(BMP-2),Msx2,Wnt3a和Wnt7a mRNA,并导致主动脉钙积累增加。用TNF-α中和抗体英夫利昔单抗治疗可消除主动脉BMP-2-Msx2-Wnt3a和Wnt7a信号传导,并显着减轻主动脉钙积累。 SM22-TNF-α转基因增强血管TNF-α的小鼠上调主动脉Msx2-Wnt3a / Wnt7a轴。此外,SM22-TNF-alphaTg; TOPGAL小鼠比主动脉和冠状动脉中的TOPGAL兄弟姐妹表现出更大的β-半乳糖苷酶报告基因染色,这表明壁画Wnt信号响应TNF-alpha增强。因此,炎性TNF-α信号促进2型DM中的主动脉成骨Msx2-Wnt程序,并且该模型中的动脉钙化是TNF-α驱动的Wnt病。建立了TNF-α在糖尿病血管钙化中的作用后,存在尚未得到满足的需要来评估CKD相关钙化模型中TNF-α和Msx2-Wnt信号的作用。如果在这些模型中得到验证,那么这些发现将具有重要的治疗应用。

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