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Aortic Msx2-Wnt Calcification Cascade Is Regulated by TNF-α–Dependent Signals in Diabetic Ldlr −/− Mice

2007; Lippincott Williams & Wilkins; Volume: 27; Issue: 12 Linguagem: Inglês

10.1161/atvbaha.107.153668

1524-4636

Ziyad Al‐Aly, Jian-Su Shao, Chung‐Fang Lai, Emily Huang, Jun Cai, Abraham Behrmann, Su‐Li Cheng, Dwight A. Towler,

Cell Adhesion Molecules Research

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-α 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-α in Ldlr −/− mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2 , Msx2 , Wnt3a , and Wnt7a . Dosing with the TNF-α 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-α augmented by a transgene ( SM22-TNFαTg ) driven from the SM22 promoter upregulated aortic Msx2 , Wnt3a , and Wnt7a. Furthermore, SM22-TNFαTg;TOPGAL mice exhibited greater aortic β-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF-α upregulated Msx2 , Wnt3a , Wnt7a , and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions. Conclusions— TNF-α promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.