on October 11, 2007
Published online before print October 11, 2007, doi: 10.1161/ATVBAHA.107.153668
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Submitted on May 9, 2007
Accepted on September 28, 2007
Aortic Msx2-Wnt Calcification Cascade Is Regulated By TNF-
–Dependent Signals In Diabetic Ldlr-/- Mice
Ziyad Al-Aly ;
From the Department of Medicine (Z.A.-A.), Division of Nephrology, St. Louis VA Medical Center, St. Louis University, and the Department of Medicine (J.-S.S., C.-F.L., E.H., J.C., A.B., S.-L.,C., D.A.T.), Center for Cardiovascular Research, Division of Bone & Mineral Diseases, Washington University, St. Louis, Mo.
* To whom correspondence should be addressed. E-mail: dtowler{at}im.wustl.edu.
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-
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- in Ldlr-/- mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF- 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- augmented by a transgene (SM22-TNFTg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNFTg;TOPGAL mice exhibited greater aortic 
-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF- upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions.
Conclusions—TNF- signals promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM.
Key words: aortic calcification • Wnt • TNF-
•
metabolic syndrome •
diabetes
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