Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 27, Issue 12, Pages 2589-2596Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.153668
Keywords
aortic calcification; Wnt; TNF-alpha; metabolic syndrome; diabetes
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Funding
- NHLBI NIH HHS [HL81138, R01 HL081138, HL69229, R01 HL069229-07, P01HL030568, R01 HL088651, R01 HL069229, R01 HL081138-01] Funding Source: Medline
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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.
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