MRP-14 and Cardiovascular Disease

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DESCRIPTION (provided by applicant): Acute myocardial infarction (AMI) commonly results from atherosclerotic plaque disruption and thrombosis. Platelets constitute a major component of such thrombi, yet the precise molecular events that immediately precede AMI remain uncertain. Transcriptional profiling can yield unbiased, mechanistic disease insights. However, gene expression following AMI may reflect either triggering events or downstream consequences of plaque rupture and thrombosis. Generated from cytoplasmic extensions from megakaryocytes, platelets retain megakaryocyte-derived mRNAs. Since platelets are anuclear, the platelet transcriptome mirrors megakaryocyte-derived mRNAs. Thus, transcriptional profiling of platelets 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) or stable coronary artery disease (CAD). Platelets isolated from STEMI and CAD patients contained 54 transcripts that were differentially expressed. One of the strongest discriminators of STEMI in the micorarrays was myeloid-related protein-14 (MRP-14) (P=0.002). MRP-14 is a member of the S100-family of Ca2+modulated proteins that modulate calcium signaling, cytoskeletal reorganization, and leukocyte trafficking. Plasma levels of MRP-8/14 heterodimer were higher in STEMI patients (P<0.001). In a prospective, nested case-control study among apparently healthy women, the risk of a first cardiovascular (CV) event increased with each increasing quartile of MRP-8/14 such that women with the highest levels had a 4-fold increase risk of any CV event (P<0.001). Risks were independent of standard risk factors and CRP. Furthermore, preliminary data indicate that MRP-8/14 protein is present in platelets and deficiency of MRP-14 reduces platelet-mediated thrombosis. These findings are the basis for this revised translational application. The central hypotheses of this proposal are that MRP-14 modulates platelet and leukocyte functions in vascular injury and thrombosis and that plasma level of MRP-8/14 serves as a useful predictor of CV events. The overall objective of this proposal is to define the role of MRP-14 in CV disease. Our specific aims are: (1) To examine whether MRP-14 modulates platelet and leukocyte functions in vitro; (2) To investigate the role of MRP-14 in vascular injury and thrombosis using wild-type and MRP-14-deficient mice; and (3) To determine whether MRP-8/14 predicts the risk of recurrent CV events in patients presenting with acute coronary syndromes using a prospective, nested case-control study from PROVE IT-TIMI-22. The experiments outlined in this proposal should clarify the role of MRP-14 in vascular injury and thrombosis. Because inflammation plays a critical role in atherosclerosis, understanding the molecular and cellular mechanisms of vascular inflammation will provide insights necessary to develop novel strategies for predicting and treating atherothrombotic events.