S100A12 mediates aortic wall remodeling and aortic aneurysm.
BACKGROUND
S100A12 is a small calcium binding protein that is a ligand of RAGE (receptor for advanced glycation end products). RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear.


OBJECTIVE
To test the role of S100A12 in vascular inflammation, we generated and analyzed mice expressing human S100A12 in vascular smooth muscle under control of the smooth muscle 22alpha promoter because S100A12 is not present in mice.


RESULTS
Transgenic mice displayed pathological vascular remodeling with aberrant thickening of the aortic media, disarray of elastic fibers, and increased collagen deposition, together with increased latent matrix metalloproteinase-2 protein and reduction in smooth muscle stress fibers leading to a progressive dilatation of the aorta. In primary aortic smooth muscle cell cultures, we found that S100A12 mediates increased interleukin-6 production, activation of transforming growth factor beta pathways and increased metabolic activity with enhanced oxidative stress. To correlate our findings to human aortic aneurysmal disease, we examined S100A12 expression in aortic tissue from patients with thoracic aortic aneurysm and found increased S100A12 expression in vascular smooth muscle cells.


CONCLUSIONS
S100A12 expression is sufficient to activate pathogenic pathways through the modulation of oxidative stress, inflammation and vascular remodeling in vivo.
Hofmann Bowman
Marion
M
Department of Medicine, Section of Cardiology, University of Chicago, Chicago, IL 60637, USA. mhofmann@medicine.bsd.uchicago.edu
Wilk
Jeannine
J
Heydemann
Ahlke
A
Kim
Gene
G
Rehman
Jalees
J
Lodato
Joseph A
JA
Raman
Jai
J
McNally
Elizabeth M
EM
D000818:Animals; D001014:Aortic Aneurysm / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000096:biosynthesis* / Q000235:genetics; D000067616:S100A12 Protein; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality
D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D016212:Transforming Growth Factor beta; D003094:Collagen