Acute myocardial infarction (AMI) triggers mobilization of stem cells from bone marrow (BM) into peripheral blood (PB). Based on our observation that the bioactive sphingophospholipids, sphingosine-1 phosphate (S1P), and ceramide-1 phosphate (C1P) regulate trafficking of hematopoietic stem cells (HSCs), we explored whether they also direct trafficking of non-hematopoietic stem cells (non-HSCs). We detected a 3-6-fold increase in circulating CD34 + , CD133 + , and CXCR4 + lineage-negative (Lin -)/CD45 -cells that are enriched in nonHSCs [including endothelial progenitors (EPCs) and very small embryonic-like stem cells (VSELs)] in PB from AMI patients (P < 0.05 vs. controls). Concurrently, we measured a *3-fold increase in S1P and C1P levels in plasma from AMI patients. At the same time, plasma obtained at hospital admission and 6 h after AMI strongly chemoattracted human BM-derived CD34 + /Lin -and CXCR4 + /Lin -cells in Transwell chemotaxis assays. This effect of plasma was blunted after depletion of S1P level by charcoal stripping and was further inhibited by the specific S1P1 receptor antagonist such as W146 and VPC23019. We also noted that the expression of S1P receptor 1 (S1P1), which is dominant in naïve BM, is reduced after the exposure to S1P at concentrations similar to the plasma S1P levels in patients with AMI, thus influencing the role of S1P in homing to the injured myocardium. Therefore, we examined mechanisms, other than bioactive lipids, that may contribute to the homing of BM non-HSCs to the infarcted myocardium. Hypoxic cardiac tissue increases the expression of cathelicidin and b-2 defensin, which could explain why PB cells isolated from patients with AMI migrated more efficiently to a low, yet physiological, gradient of stromal-derived factor-1 in Transwell migration assays. Together, these observations suggest that while elevated S1P and C1P levels early in the course of AMI may trigger mobilization of non-HSCs into PB, cathelicidin and b-2 defensin could play an important role in their homing to damaged myocardium.

Anaemia and RBC (red blood cell) transfusion may be associated with worse clinical outcomes, especially with longer blood storage duration prior to transfusion. The mechanisms underlying these harmful effects are unknown. RBCs have been proposed to buffer plasma S1P (sphingosine 1-phosphate), a lysophospholipid essential for the maintenance of endothelial integrity and important in the regulation of haematopoietic cell trafficking. The present study examined the effect of anaemia, RBC transfusion and RBC storage duration on plasma S1P levels. Plasma S1P from 30 individuals demonstrated a linear correlation with Hct (haematocrit; R2=0.51, P<0.001) with no evidence for a plateau at Hct values as low as 19%. RBC transfusion in 23 anaemic patients with baseline mean Hct of 22.2±0.34% (value is the mean±S.D.) increased Hct to 28.3±0.6% at 72 h. Despite an Hct increase, RBC transfusion failed to elevate plasma S1P consistently. A trend towards an inverse correlation was observed between RBC storage duration and the post-transfusion increase in plasma S1P. After 30 days of storage, RBC S1P decreased to 19% of that observed in fresh (3–7-day-old) RBC segments. RBC membranes contain low levels of both S1P phosphatase and S1P lyase activities that may account for the decline in S1P levels with storage. Our results support a role for RBCs in buffering plasma S1P and identify a disturbance in the capacity after transfusion. Changes in S1P content may contribute to an RBC storage lesion. Further studies should investigate the clinical significance of alterations in circulating S1P levels and the potential value of enriching stored RBCs with S1P.

of vascular cell function by bioactive lysophospholipids. J Throm Haemost, 7 (Suppl. 1): 38-43.Summary. Lysophosphatidic acid (LPA), its sphingolipid homolog sphingosine 1-phosphate (S1P) and several other related molecules constitute a family of bioactive lipid phosphoric acids that function as receptor-active mediators with roles in cell growth, differentiation, inflammation, immunomodulation, apoptosis and development. LPA and S1P are present in physiologically relevant concentrations in the circulation. In isolated cell culture systems or animal models, these lipids exert a range of effects that suggest that S1P and LPA could play important roles in maintaining normal vascular homeostasis and in vascular injury responses. LPA and S1P act on a series of G protein-coupled receptors, and LPA may also be an endogenous regulator of PPARc activity. In this review, we discuss potential roles for lysolipid signaling in the vasculature and mechanisms by which these bioactive lipids could contribute to cardiovascular disease.

Both catheter-directed thrombolysis (CDT) and ultrasound-assisted thrombolysis (USAT) are novel treatment modalities for patients presenting with acute pulmonary embolism (PE). The objective of this study was to compare clinical and quality-of-life (QOL) outcomes for patients undergoing either treatment modality. We retrospectively studied 70 consecutive patients treated with either CDT or USAT over 3 years at a multicenter health system. The primary clinical efficacy endpoint was right ventricular systolic pressure (RVSP) reduction post-procedurally. Safety endpoints were mortality and bleeding incidents based on Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO) criteria. Long-term QOL was assessed using the 36-Item Short-Form Health Survey (SF-36) via phone interview. Thirty-seven patients (53%) in our study underwent USAT and 33 (47%) patients were treated with conventional CDT. Among all patients studied, 96% had echocardiographic evidence for right ventricular strain on admission. Mean RVSP decreased by 18 ± 13 mmHg in the USAT group post-procedurally as compared to 14 ± 16 mmHg in the CDT group, without significant difference between groups (p = 0.31). Rates of moderate and severe bleeding were largely identical between USAT and CDT groups (USAT: 3%; CDT: 0%; p = 0.09). There was no death in either group during admission. At long-term follow-up, there was no significant difference in QOL between both treatment modalities in all eight functional domains of SF-36. Our retrospective study demonstrated using USAT over conventional CDT for acute submassive or massive PE did not yield additional clinical, safety, or long-term QOL benefit.