Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice

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

Research output: Contribution to journalArticle

206 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2589-2596
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume27
Issue number12
DOIs
StatePublished - Dec 1 2007

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Alkaline Phosphatase
Haptoglobins
Obesity
High Fat Diet
Calcium
Hyperglycemia
Galactosidases
Tunica Media
Myofibroblasts
Hypercholesterolemia
Hyperlipidemias
Neutralizing Antibodies
Serum
Transgenes
Type 2 Diabetes Mellitus
Blood Vessels
Down-Regulation
Staining and Labeling
Cytokines
Morbidity

Keywords

  • Aortic calcification
  • Diabetes
  • Metabolic syndrome
  • TNF-α
  • Wnt

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice. / Al-Aly, Ziyad; Shao, Jian Su; Lai, Chung Fang; Huang, Emily; Cai, Jun; Behrmann, Abraham; Cheng, Su Li; Towler, Dwight A.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 27, No. 12, 01.12.2007, p. 2589-2596.

Research output: Contribution to journalArticle

Al-Aly, Ziyad ; Shao, Jian Su ; Lai, Chung Fang ; Huang, Emily ; Cai, Jun ; Behrmann, Abraham ; Cheng, Su Li ; Towler, Dwight A. / Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2007 ; Vol. 27, No. 12. pp. 2589-2596.
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T1 - Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice

AU - Al-Aly, Ziyad

AU - Shao, Jian Su

AU - Lai, Chung Fang

AU - Huang, Emily

AU - Cai, Jun

AU - Behrmann, Abraham

AU - Cheng, Su Li

AU - Towler, Dwight A.

PY - 2007/12/1

Y1 - 2007/12/1

N2 - 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.

AB - 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.

KW - Aortic calcification

KW - Diabetes

KW - Metabolic syndrome

KW - TNF-α

KW - Wnt

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