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

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 with Ad-Nnat increased expression of a panel of NFκ B regulated genes including inflammatory cytokines, chemokines and cell adhesion molecules. Infection of mouse carotid arteries in vivo with the Ad-Nnat increased expression of VCAM-1 protein. Nnat activation of NFκ B and inflammatory gene expression in HAEC was mediated through pathways distinct from TNF-α. Nnat expression stimulated p38, JNK, ERK and AKT kinase phosphorylation. PI3K and p38 inhibitors prevented Nnat mediated activation of NFκ B 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.