S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program.
OBJECTIVE
The proinflammatory cytokine S100A12 is associated with coronary atherosclerotic plaque rupture. We previously generated transgenic mice with vascular smooth muscle-targeted expression of human S100A12 and found that these mice developed aortic aneurysmal dilation of the thoracic aorta. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)-null mice would accelerate atherosclerosis.


RESULTS
ApoE-null mice with or without the S100A12 transgene were analyzed. We found a 1.4-fold increase in atherosclerotic plaque size and more specifically a large increase in calcified plaque area (45% versus 7% of innominate artery plaques and 18% versus 10% of aortic root plaques) in S100A12/ApoE-null mice compared with wild-type/ApoE-null littermates. Expression of bone morphogenic protein and other osteoblastic genes was increased in aorta and cultured vascular smooth muscle, and importantly, these changes in gene expression preceded the development of vascular calcification in S100A12/ApoE-null mice. Accelerated atherosclerosis and vascular calcification were mediated, at least in part, by oxidative stress because inhibition of NADPH oxidase attenuated S100A12-mediated osteogenesis in cultured vascular smooth muscle cells. S100A12 transgenic mice in the wild-type background (ApoE+/+) showed minimal vascular calcification, suggesting that S100A12 requires a proinflammatory/proatherosclerotic environment to induce osteoblastic differentiation and vascular calcification.


CONCLUSIONS
Vascular smooth muscle S100A12 accelerates atherosclerosis and augments atherosclerosis-triggered osteogenesis, reminiscent of features associated with plaque instability.
Department of Medicine, Section of Cardiology, University of Chicago, 5841 S Maryland Avenue, Chicago IL 60637, USA. mhofmann@medicine.bsd.uchicago.edu
Marion A
MA
Hofmann Bowman
Joseph
J
Gawdzik
Usama
U
Bukhari
Aliya N
AN
Husain
Peter T
PT
Toth
Gene
G
Kim
Judy
J
Earley
Elizabeth M
EM
McNally
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002114:Calcinosis / Q000503:physiopathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D000067616:S100A12 Protein; D015398:Signal Transduction / Q000502:physiology
D001057:Apolipoproteins E; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D019255:NADPH Oxidases