Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-Dependent signals in diabetic Ldlr-/- mice
Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-Dependent signals in diabetic Ldlr-/- mice
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DOI：
10.1161/atvbaha.107.153668
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发表时间：
2007-12-01
影响因子：
8.7
通讯作者：
Towler, Dwight A.
中科院分区：
文献类型：
--
作者：
Al-Aly, Ziyad;Shao, Jian-Su;Towler, Dwight A.
目的：主动脉钙化在2型糖尿病(T2 DM)中普遍存在，增加发病率并追踪代谢综合征参数。喂食高脂“西化”饮食(HFD)的LDLR(-/-)小鼠主要通过成骨形态原和诱导主动脉碱性磷酸酶(ALP)的转录程序，在中膜中积累主动脉钙。由于升高的肿瘤坏死因子-α是2型糖尿病肥胖的特征，我们检测了这种炎性细胞因子的作用。方法和结果--高脂饲料促进肥胖、高血糖和高脂血症，并上调血清肿瘤坏死因子-α。血清结合珠蛋白(炎症标志物)随着BMP2、MSX2、WNT3a和WNT7a的表达而升高。给予肿瘤坏死因子-α中和抗体英夫利昔单抗不能减少肥胖、高胆固醇血症或高血糖；然而，英夫利昔单抗可下调结合珠蛋白、主动脉BMP2、MSX2、WNT3a和WNT7a以及主动脉钙积聚。由SM22启动子驱动的转基因(SM22-TNFαTG)增强血管肿瘤坏死因子-α的小鼠上调了主动脉MSX2、WNT3a和WNT7a的表达。此外，与TOPGAL同胞相比，SM22-TNFαTG；TOPGAL小鼠表现出更大的主动脉β-半乳糖苷酶报告染色，表明壁上Wnt信号增强。在培养的主动脉肌成纤维细胞中，肿瘤坏死因子-α上调MSX2、WNT3a、WNT7a和ALP。结论肿瘤坏死因子-α可促进T2 DM大鼠主动脉MSX2-WNT程序，参与T2 DM大鼠主动脉钙蓄积。
Objective-Aortic calcification is prevalent in type II diabetes (T2DM), enhancing morbidity and tracking metabolic syndrome parameters. Ldlr(-/-) mice fed high-fat "Westernized" diets (HFD) accumulate aortic calcium primarily in the tunica media, mediated via osteogenic morphogens and transcriptional programs that induce aortic alkaline phosphatase (ALP). Because elevated TNF-alpha is characteristic of obesity with T2DM, we examined contributions of this inflammatory cytokine.Methods and Results-HFD promoted obesity, hyperglycemia, and hyperlipidemia, and upregulated serum TNF-alpha in Ldlr(-/-) mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF-alpha neutralizing antibody infliximab did not reduce obesity, hypercholesterolemia, or hyperglycemia; however, haptoglobin, aortic BMP2, Msx2, Wnt3a, and Wnt7a and aortic calcium accumulation were downregulated by infliximab. Mice with vascular TNF-alpha augmented by a transgene (SM22-TNF alpha Tg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNF alpha Tg;TOPGAL mice exhibited greater aortic beta-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF-alpha upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions.Conclusions-TNF-alpha promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.