Louisville, KY, United States
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Selim S.,The Gill Heart Institute | Sunkara M.,The Gill Heart Institute | Salous A.K.,The Gill Heart Institute | Leung S.W.,The Gill Heart Institute | And 9 more authors.
Clinical Science | Year: 2011

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. © 2011 The Author(s).


Zheng Y.,Graduate Center for Nutritional science | Morris A.,The Gill Heart Institute | Sunkara M.,The Gill Heart Institute | Layne J.,Graduate Center for Nutritional science | And 2 more authors.
Journal of Nutritional Biochemistry | Year: 2012

Flavonoids, such as the tea catechin epigallocatechin-gallate (EGCG), can protect against atherosclerosis by decreasing vascular endothelial cell inflammation. Heme oxygenase-1 (HO-1) is an enzyme that plays an important role in vascular physiology, and its induction may provide protection against atherosclerosis. Heme oxygenase-1 can be compartmentalized in caveolae in endothelial cells. Caveolae are plasma microdomains important in vesicular transport and the regulation of signaling pathways associated with the pathology of vascular diseases. We hypothesize that caveolae play a role in the uptake and transport of EGCG and mechanisms associated with the anti-inflammatory properties of this flavonoid. To test this hypothesis, we explored the effect of EGCG on the induction of NF-E2-related factor (Nrf2) and HO-1 in endothelial cells with or without functional caveolae. Treatment with EGCG activated Nrf2 and increased HO-1 expression and cellular production of bilirubin. In addition, EGCG rapidly accumulated in caveolae, which was associated with caveolin-1 displacement from the plasma membrane towards the cytosol. Similar to EGCG treatment, silencing of caveolin-1 by siRNA technique also resulted in up-regulation of Nrf2, HO-1 and bilirubin production. These data suggest that EGCG-induced caveolin-1 displacement may reduce endothelial inflammation. © 2012 Elsevier Inc.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Current cardiology reviews | Year: 2016

HMG CoA reductase inhibitors, or statins, are standard of care for preventing cardiovascular disease in at-risk populations. Statins are a well-established therapy proven to reduce long-term cardiovascular mortality and morbidity for prevention of secondary cardiovascular events and have become guidelinerecommended therapy following acute myocardial infarction. Emerging data from clinical trials over the last decade indicates that statin therapy may provide broad beneficial effects beyond their primary lipid lowering mechanisms. In coronary heart disease, statins have demonstrated a unique ability to target several cellular pathways, which appear to play an underappreciated role in acute inflammation and subsequent thrombosis. Herein, we review the potential mechanisms where statins may act as antithrombotic agents in the setting of acute coronary syndromes and discuss the clinical implications of these findings.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2011

Autotaxin (ATX) is a secreted lysophospholipase D that generates the bioactive lipid mediator lysophosphatidic acid (LPA). We and others have reported that ATX binds to integrins, but the function of ATX-integrin interactions is unknown. The recently reported crystal structure of ATX suggests a role for the solvent-exposed surface of the N-terminal tandem somatomedin B-like domains in binding to platelet integrin IIb(3). The opposite face of the somatomedin B-like domain interacts with the catalytic phosphodiesterase (PDE) domain to form a hydrophobic channel through which lysophospholipid substrates enter and leave the active site. Based on this structure, we hypothesize that integrin-bound ATX can access cell surface substrates and deliver LPA to cell surface receptors. To test this hypothesis, we investigated the integrin selectivity and signaling pathways that promote ATX binding to platelets. We report that both platelet 1 and 3 integrins interact in an activation-dependent manner with ATX via the SMB2 domain. ATX increases thrombin-stimulated LPA production by washed platelets ~10-fold. When incubated under conditions to promote integrin activation, ATX generates LPA from CHO cells primed with bee venom phospholipase A(2), and ATX-mediated LPA production is enhanced more than 2-fold by CHO cell overexpression of integrin (3). The effects of ATX on platelet and cell-associated LPA production, but not hydrolysis of small molecule or detergent-solubilized substrates, are attenuated by point mutations in the SMB2 that impair integrin binding. Integrin binding therefore localizes ATX activity to the cell surface, providing a mechanism to generate LPA in the vicinity of its receptors.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Current drug targets | Year: 2014

Venous thrombosis is a common medical disorder affecting nearly one million Americans each year. This review will focus primarily on the formation of venous thrombosis as well as current and future treatment options. While the full pathophysiology of venous thrombosis is not known, recent evidence points to a role for von Willebrand Factor, platelets, and neutrophils in thrombus formation. Many laboratory and imaging tests may be used for the diagnosis of venous thrombosis (VTE), but risk factor identification and clinical examination should not be overlooked as they are vital in assuring accurate treatment and patient identification. Historically heparin followed by a vitamin K antagonist has been the standard of care for treatment of VTE, but increasing data involving factor Xa inhibitors and direct thrombin inhibitors may mean a shift in first-line therapy in the very near future. Invasive therapies such as catheter-directed thrombolysis have also shown promise in the treatment of venous thrombosis and will likely see increased use in the future.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Arteriosclerosis, thrombosis, and vascular biology | Year: 2012

The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses.We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury.Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Biochimica et biophysica acta | Year: 2012

Lipid phosphate phosphatases (LPP) are integral membrane proteins with broad substrate specificity that dephosphorylate lipid substrates including phosphatidic acid, lysophosphatidic acid, ceramide 1-phosphate, sphingosine 1-phosphate, and diacylglycerol pyrophosphate. Although the three mammalian enzymes (LPP1-3) demonstrate overlapping catalytic activities and substrate preferences in vitro, the phenotypes of mice with targeted inactivation of the Ppap2 genes encoding the LPP enzymes reveal nonredundant functions. A specific role for LPP3 in vascular development has emerged from studies of mice lacking Ppap2b. A meta-analysis of multiple, large genome-wide association studies identified a single nucleotide polymorphism in PPAP2B as a novel predictor of coronary artery disease. In this review, we will discuss the evidence that links LPP3 to vascular development and disease and evaluate potential molecular mechanisms. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.


PubMed | The Gill Heart Institute
Type: | Journal: Advances in hematology | Year: 2012

Anemia and resultant red blood cell transfusion may be associated with adverse long-term clinical outcomes. To investigate the mechanism(s) responsible, we profiled inflammatory biomarkers and circulating levels of the bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) in control and anemic mice with or without LPS-induced systemic inflammation. Acute anemia or lipopolysaccharide (LPS) challenge alone triggered an increase of circulating levels of the inflammatory markers IL-6 and keratinocyte-derived chemokine (CXCL1/KC). Moreover, administration of LPS to anemic mice reduced circulating S1P levels and augmented lung injury and pulmonary vascular permeability. Transfusion of aged, but not fresh, red blood cells (RBCs) worsened pulmonary vascular leak. S1P levels decline markedly during storage of mouse RBCs. Loading stored murine RBCs with S1P prior to transfusion partially attenuated anemia-associated acute pulmonary vascular leak. Taken together, our results indicate that anemia and systemic inflammation can alter the S1P buffering capacity of RBCs, suggesting possible strategies for alleviating transfusion-related lung injury in clinical practice.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Thrombosis research | Year: 2011

Platelets occupy a central role at the interface between thrombosis and inflammation. At sites of vascular damage, adherent platelets physically and functionally interact with circulating leukocytes. Activated platelets release soluble factors into circulation that may have local and systemic effects on blood and vascular cells. Platelets can also interact with a wide variety of microbial pathogens. Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes involving tissue injury, immune responses and repair that underlie diverse diseases such as atherosclerosis, autoimmune disorders, inflammatory lung and bowel disorders, host-defense responses and sepsis. In this review, we summarize the general mechanisms by which platelets may contribute to immune function, and then discuss evidence for their role in host defense responses and sepsis from preclinical and clinical studies.


PubMed | The Gill Heart Institute
Type: Journal Article | Journal: Clinical science (London, England : 1979) | Year: 2011

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.

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