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(Circulation. 2009;120:427-436.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Myeloid-Related Protein-8/14 Is Critical for the Biological Response to Vascular Injury

Kevin Croce, MD, PhD; Huiyun Gao, MD; Yunmei Wang, PhD; Toshifumi Mooroka, MD; Masashi Sakuma, MD; Can Shi, PhD; Galina K. Sukhova, PhD; René R.S. Packard, MD; Nancy Hogg, PhD; Peter Libby, MD; Daniel I. Simon, MD

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (K.C., G.K.S., R.R.S.P., P.L.); University Hospitals Case Medical Center, Case Cardiovascular Center, Case Western Reserve University School of Medicine, Cleveland, Ohio (K.C., H.G., Y.W., T.M., M.S., C.S., D.I.S.); Cancer Research UK, London, England (N.H.); and VA Boston Healthcare System, Boston, Mass (K.C.).

Correspondence to Daniel I. Simon, MD, 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. E-mail Daniel.Simon{at}UHhospitals.org

Received August 15, 2008; accepted March 26, 2009.

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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