Myeloid-related protein-8/14 is critical for the biological response to vascular injury.
BACKGROUND
Myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) are members of the S100 family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of Toll-like receptor-4 and the receptor for advanced glycation end products. A transcriptional profiling approach in patients with acute coronary syndromes identified MRP-14 as a novel predictor of myocardial infarction. Further studies demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Beyond its serving as a risk marker, whether MRP-8/14 participates directly in vascular inflammation and disease remains unclear.


RESULTS
We evaluated vascular inflammation in wild-type and MRP-14-deficient (MRP-14(-/-)) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14(-/-) mice had significant reductions in leukocyte accumulation, cellular proliferation, and neointimal formation compared with wild-type mice. In a cytokine-induced local Shwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14(-/-) mice had significant reductions in neutrophil accumulation, lesion severity, and hemorrhagic area. In response to high-fat feeding, mice doubly deficient in apolipoprotein E and MRP-8/14 complexes had attenuation in atherosclerotic lesion area and in macrophage accumulation in plaques compared with mice deficient in apolipoprotein E alone.


CONCLUSIONS
This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.
Croce
Kevin
K
Director, Case Cardiovascular Center, Herman K. Hellerstein Professor of Cardiovascular Research, Case Western Reserve University School of Medicine, Division of Cardiovascular Medicine, 11100 Euclid Ave, LKS 3001, Cleveland, OH 44106-5038, USA.
Gao
Huiyun
H
Wang
Yunmei
Y
Mooroka
Toshifumi
T
Sakuma
Masashi
M
Shi
Can
C
Sukhova
Galina K
GK
Packard
René R S
RR
Hogg
Nancy
N
Libby
Peter
P
Simon
Daniel I
DI
D000818:Animals; D001794:Blood Pressure; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000276:immunology / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005263:Femoral Artery / Q000276:immunology / Q000293:injuries* / Q000473:pathology; D006470:Hemorrhage / Q000276:immunology / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D013927:Thrombosis / Q000276:immunology / Q000473:pathology; D017539:Tunica Intima / Q000276:immunology / Q000293:injuries / Q000473:pathology; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D040501:Calgranulin A; D040502:Calgranulin B; D008055:Lipids