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Neuronatin: a new inflammation gene expressed on the aortic endothelium of diabetic mice.

Mzhavia N, Yu S, Ikeda S, Chu TT, Goldberg I, Dansky HM - Diabetes (2008)

Bottom Line: Nnat expression stimulated p38, Jun NH(2)-terminal kinase, extracellular signal-related kinase, and AKT kinase phosphorylation.Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-kappaB-induced gene expression.The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Columbia University, New York, New York, USA. nm2170@columbia.edu

ABSTRACT

Objective: Identification of arterial genes and pathways altered in obesity and diabetes.

Research design and methods: Aortic gene expression profiles of obese and diabetic db/db, high-fat diet-fed C57BL/6J, and control mice were obtained using mouse Affymetrix arrays. Neuronatin (Nnat) was selected for further analysis. To determine the function of Nnat, a recombinant adenovirus (Ad-Nnat) was used to overexpress the Nnat gene in primary endothelial cells and in the mouse aorta in vivo.

Results: Nnat, a gene of unknown vascular function, was upregulated in the aortas of db/db and high-fat diet-fed mice. Nnat gene expression was increased in db/db mouse aorta endothelial cells. Nnat protein was localized to aortic endothelium and was selectively increased in the endothelium of db/db mice. Infection of primary human aortic endothelial cells (HAECs) with Ad-Nnat increased expression of a panel of nuclear factor-kappaB (NF-kappaB)-regulated genes, including inflammatory cytokines, chemokines, and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of vascular cell adhesion molecule 1 protein. Nnat activation of NF-kappaB and inflammatory gene expression in HAECs was mediated through pathways distinct from tumor necrosis factor-alpha. Nnat expression stimulated p38, Jun NH(2)-terminal kinase, extracellular signal-related kinase, and AKT kinase phosphorylation. Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-kappaB-induced gene expression.

Conclusions: Nnat expression is increased in endothelial cells of obese and diabetic mouse blood vessels. The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.

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Adenovirus-mediated expression of Nnat in mouse carotid arteries induced expression of VCAM-1. Immunohistochemical staining of C57BL/6J mouse carotid arteries for Nnat (A) and VCAM-1 (B) protein after incubation of blood vessels with Ad-Nnat or Ad-GFP adenovirus. C: Integrated intensity of endothelial cell staining. n = 4–7; *P < 0.05. (Please see http://dx.doi.org/10.2337/db07-1746 for a high-quality digital representation of this image.)
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f5: Adenovirus-mediated expression of Nnat in mouse carotid arteries induced expression of VCAM-1. Immunohistochemical staining of C57BL/6J mouse carotid arteries for Nnat (A) and VCAM-1 (B) protein after incubation of blood vessels with Ad-Nnat or Ad-GFP adenovirus. C: Integrated intensity of endothelial cell staining. n = 4–7; *P < 0.05. (Please see http://dx.doi.org/10.2337/db07-1746 for a high-quality digital representation of this image.)

Mentions: To test whether Nnat can induce adhesion molecule expression in endothelium in vivo, Ad-Nnat or Ad-GFP was injected into carotid arteries of C57BL/6J wild-type mice. Mouse arteries were harvested 2 days after infection, and arterial sections were processed for determination of immunoreactive Nnat and VCAM-1. Ad-Nnat increased the intensity of staining for the Nnat protein in the endothelium approximately fourfold. Staining for VCAM-1 increased by ninefold compared with staining of arteries that had been infected with Ad-GFP (Fig. 5). These data demonstrate that expression of Nnat in endothelium induces endothelial expression of adhesion molecules in vivo.


Neuronatin: a new inflammation gene expressed on the aortic endothelium of diabetic mice.

Mzhavia N, Yu S, Ikeda S, Chu TT, Goldberg I, Dansky HM - Diabetes (2008)

Adenovirus-mediated expression of Nnat in mouse carotid arteries induced expression of VCAM-1. Immunohistochemical staining of C57BL/6J mouse carotid arteries for Nnat (A) and VCAM-1 (B) protein after incubation of blood vessels with Ad-Nnat or Ad-GFP adenovirus. C: Integrated intensity of endothelial cell staining. n = 4–7; *P < 0.05. (Please see http://dx.doi.org/10.2337/db07-1746 for a high-quality digital representation of this image.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551689&req=5

f5: Adenovirus-mediated expression of Nnat in mouse carotid arteries induced expression of VCAM-1. Immunohistochemical staining of C57BL/6J mouse carotid arteries for Nnat (A) and VCAM-1 (B) protein after incubation of blood vessels with Ad-Nnat or Ad-GFP adenovirus. C: Integrated intensity of endothelial cell staining. n = 4–7; *P < 0.05. (Please see http://dx.doi.org/10.2337/db07-1746 for a high-quality digital representation of this image.)
Mentions: To test whether Nnat can induce adhesion molecule expression in endothelium in vivo, Ad-Nnat or Ad-GFP was injected into carotid arteries of C57BL/6J wild-type mice. Mouse arteries were harvested 2 days after infection, and arterial sections were processed for determination of immunoreactive Nnat and VCAM-1. Ad-Nnat increased the intensity of staining for the Nnat protein in the endothelium approximately fourfold. Staining for VCAM-1 increased by ninefold compared with staining of arteries that had been infected with Ad-GFP (Fig. 5). These data demonstrate that expression of Nnat in endothelium induces endothelial expression of adhesion molecules in vivo.

Bottom Line: Nnat expression stimulated p38, Jun NH(2)-terminal kinase, extracellular signal-related kinase, and AKT kinase phosphorylation.Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-kappaB-induced gene expression.The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Columbia University, New York, New York, USA. nm2170@columbia.edu

ABSTRACT

Objective: Identification of arterial genes and pathways altered in obesity and diabetes.

Research design and methods: Aortic gene expression profiles of obese and diabetic db/db, high-fat diet-fed C57BL/6J, and control mice were obtained using mouse Affymetrix arrays. Neuronatin (Nnat) was selected for further analysis. To determine the function of Nnat, a recombinant adenovirus (Ad-Nnat) was used to overexpress the Nnat gene in primary endothelial cells and in the mouse aorta in vivo.

Results: Nnat, a gene of unknown vascular function, was upregulated in the aortas of db/db and high-fat diet-fed mice. Nnat gene expression was increased in db/db mouse aorta endothelial cells. Nnat protein was localized to aortic endothelium and was selectively increased in the endothelium of db/db mice. Infection of primary human aortic endothelial cells (HAECs) with Ad-Nnat increased expression of a panel of nuclear factor-kappaB (NF-kappaB)-regulated genes, including inflammatory cytokines, chemokines, and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of vascular cell adhesion molecule 1 protein. Nnat activation of NF-kappaB and inflammatory gene expression in HAECs was mediated through pathways distinct from tumor necrosis factor-alpha. Nnat expression stimulated p38, Jun NH(2)-terminal kinase, extracellular signal-related kinase, and AKT kinase phosphorylation. Phosphatidylinositol 3-kinase and p38 inhibitors prevented Nnat-mediated activation of NF-kappaB-induced gene expression.

Conclusions: Nnat expression is increased in endothelial cells of obese and diabetic mouse blood vessels. The effects of Nnat on inflammatory pathways in vitro and in vivo suggest a pathophysiological role of this new gene in diabetic vascular diseases.

Show MeSH
Related in: MedlinePlus