Abstract
Platelets participate in events that immediately precede acute myocardial infarction. Because platelets lack nuclear DNA but retain megakaryocyte-derived mRNAs, the platelet transcriptome provides a novel window on gene expression preceding acute coronary events. We profiled platelet mRNA from patients with acute ST-segment–elevation myocardial infarction (STEMI, n=16) or stable coronary artery disease (n=44). The platelet transcriptomes were analyzed and single-gene models constructed to identify candidate genes with differential expression. We validated one candidate gene product by performing a prospective, nested case-control study (n=255 case-control pairs) among apparently healthy women to assess the risk of future cardiovascular events (nonfatal MI, nonfatal stroke, and cardiovascular death) associated with baseline plasma levels of the candidate protein. Platelets isolated from STEMI and coronary artery disease patients contained 54 differentially expressed transcripts. The strongest discriminators of STEMI in the microarrays were CD69 (odds ratio 6.2, P<0.001) and myeloid-related protein-14 (MRP-14 also known as S100A8/A9; odds ratio 3.3, P=0.002). In the validation study, the risk of a first cardiovascular event increased with each increasing quartile of MRP-8/14 (P trend <0.001) such that women with the highest levels had a 3.8-fold increase in risk of any vascular event (P<0.001). 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. These findings indicate that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment. However, a causal role for MRP-14 in thrombosis has not been established and a viable molecular mechanism remains unknown. Here we show that time to thrombotic occlusion was prolonged markedly in MRP-14-/- mice. We observed that MRP-14 and MRP-8/14 are expressed in, and secreted by platelets, and that thrombus formation is reduced in whole blood from MRP-14-/- mice. Infusion of WT platelets or purified MRP-14 (or MRP-8/14) into MRP-14-/- mice shortened the carotid artery occlusion time, indicating that platelet-derived MRP-14 directly regulates thrombosis. Thus, a new pathway of inflammation and thrombosis involving MRP-14 is identified. MRP-14 represents a novel target for treating atherothrombotic disorders, including myocardial infarction and stroke.
Disclosures:
Simon: Cordis/J&J: Consultancy; Janssen/J&J: Consultancy; Medtronic Vascular: Consultancy; Merck: Consultancy; Medtronic Foundation: Research Funding.
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