Neuronatin: a new inflammation gene expressed on the aortic endothelium of diabetic mice.
OBJECTIVE
Identification of arterial genes and pathways altered in obesity and diabetes.


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.
Mzhavia
Nino
N
Division of Cardiology, Columbia University, New York, New York, USA. nm2170@columbia.edu
Yu
Shuiqing
S
Ikeda
Shota
S
Chu
Tehua T
TT
Goldberg
Ira
I
Dansky
Hayes M
HM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D018836:Inflammation Mediators; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018925:Chemokines; D016207:Cytokines; D004041:Dietary Fats; D018836:Inflammation Mediators; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C490239:Nnat protein, mouse; D014409:Tumor Necrosis Factor-alpha