Myeloid-related protein-8/14 is critical for the biological response to vascular injury

K Croce, H Gao, Y Wang, T Mooroka, M Sakuma… - Circulation, 2009 - Am Heart Assoc
K Croce, H Gao, Y Wang, T Mooroka, M Sakuma, C Shi, GK Sukhova, RRS Packard, N Hogg…
Circulation, 2009Am Heart Assoc
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 …
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.
Am Heart Assoc