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. Methods and 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. Conclusion— This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.

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Background : 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 RAGE. Using a transcriptional profiling approach in patients with acute coronary syndromes, we made the novel discovery that MRP-14 is associated with atherothrombosis, and demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Despite functioning as a pro-inflammatory mediator, the role of MRP-8/14 in vascular inflammation and disease are unknown. Methods and Results : We evaluated vascular inflammation in wild-type (WT) 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 a 33% reduction in leukocyte accumulation ( P =.0004) and a 72% reduction in cellular proliferation ( P =0.001) in the arterial wall followed by a 45% reduction in neointima formation ( P =0.004) compared to WT mice. In a cytokine-induced local Schwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14 −/− mice had a 59% reduction in lesion severity ( P <0.0001), an 82% smaller hemorrhagic area ( P =0.015), and a 45% decline in neutrophil accumulation ( P =0.013). Finally, in response to high-fat feeding, mice doubly deficient in ApoE and MRP-8/14 complexes had attenuation in atherosclerotic lesion area by 34% ( P =0.023) and a 60% decrease in macrophage accumulation in plaques ( P =0.021) compared to mice deficient in ApoE alone. Conclusions: This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury. Targeting MRP-8/14 may provide a novel therapeutic approach to modulate diverse forms of vascular injury, including restenosis, vasculitis, and atherosclerosis.