Genetic variants in TLR2 and TLR4 are associated with markers of monocyte activation: the Atherosclerosis Risk in Communities MRI Study.

Markers of monocyte activation play a critical role in atherosclerosis, but little is known about the genetic influences on cellular levels. Therefore, we investigated the influence of genetic variants in monocyte differentiation antigen (CD14), toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), and myeloperoxidase (MPO) on monocyte surface receptor levels. The study sample consisted of 1,817 members of a biracial cohort of adults from the Atherosclerosis Risk in Communities Carotid MRI Study.

Prostacyclin inhibits endothelial cell XIAP ubiquitination and degradation.

To understand the role of prostacyclin (PGI(2)) in protecting endothelial cells from apoptosis, we evaluated the effects of carbaprostacyclin (cPGI(2)) on H(2)O(2)-induced human umbilical vein endothelial cell (HUVEC) apoptosis. cPGI(2) suppressed H(2)O(2)-induced annexin V-positive cells in a concentration- and time-dependent manner. Pre-treatment of HUVEC with 50 microM cPGI(2) for 4 h produced the maximal anti-apoptotic effect.

Protection of endothelial survival by peroxisome proliferator-activated receptor-delta mediated 14-3-3 upregulation.

Objective: To determine the role of prostacyclin (PGI2) in protecting endothelial cells (ECs) from apoptosis and elucidate the protective mechanism.

Methods And Results: To evaluate the effect of PGI2 on EC survival, we treated ECs with Ad-COX1/PGIS (Ad-COPI), which augmented selectively PGI2 production or carbaprostacyclin (cPGI2) followed by H2O2 for 4 hours. Ad-COPI inhibited annexin V-positive cells and blocked caspase 3 activation.

Molecular aspects of thrombosis and antithrombotic drugs.

There have been major advances in our understanding of thrombosis and antithrombotic drugs. This review focuses on the molecular aspects of thrombus formation and antithrombotic therapy. Molecules involved in arterial thrombosis are derived from inflammatory cells in the atherosclerotic plaque and blood platelets.

Cyclooxygenase-2-derived endogenous prostacyclin enhances mouse embryo hatching.

Introduction: The role of prostaglandins (PGs) in embryo hatching remains controversial. In addition, there is no direct evidence that mouse embryos synthesize PGs.

Methods: The effects of endogenous PG on mouse embryo hatching were evaluated by blocking endogenous PG synthesis with indomethacin.

The variable number of tandem repeat polymorphism of platelet glycoprotein Ibalpha and risk of coronary heart disease.

Glycoprotein (GP) Ib-IX-V complex plays an important role in formation of platelet-fibrin clot at the area of damaged vessel wall. One polymorphism of GP Ibalpha, the main component of GP Ib-IX-V complex, is due to variable numbers of tandem repeats (VNTRs) in the macroglycopeptide region of this molecule. We studied the association between the presence of different VNTR alleles of GP Ibalpha and the frequency of coronary heart disease (CHD) among individuals recruited to a large community-based case-cohort study (Atherosclerosis Risk in Communities [ARIC] study).

Prostacyclin is an autocrine regulator in the contraction of oviductal smooth muscle.

Background: It was recently discovered that prostacyclin constituted 40-50% of prostaglandins (PG) produced by minced human oviduct. It is well established that prostacyclin relaxes vascular smooth muscle, but whether oviductal smooth muscle synthesizes prostacyclin and whether its contraction is affected by prostacyclin remain unclear.

Methods: Smooth muscle microdissected from human oviducts was used for the study.

Human fallopian tubes express prostacyclin (PGI) synthase and cyclooxygenases and synthesize abundant PGI.

Animal studies unequivocally support the indispensable role of prostaglandin (PG) and cyclooxygenase (COX) in ovulation and implantation. Available data also suggest that PG and COX may be important in the transport of embryos. The effects of PGE(2) and PGF(2alpha) on the contractility of human tubal muscle have been studied extensively; the expression of COX in human fallopian tubes was also reported.

Thrombomodulin: a linker of coagulation and fibrinolysis and predictor of risk of arterial thrombosis.

Thrombomodulin (TM) binds thrombin, changes thrombin conformation and allows thrombin to activate protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Activated protein C and TAFI inhibit coagulation and fibrinolysis, respectively. TM is, thus, a linker of endogenous control of coagulation and fibrinolysis.

Cell cycle-dependent expression of cyclooxygenase-2 in human fibroblasts.

The purpose of this investigation is to determine whether the levels of cyclooxygenase-2 (COX-2) expression are cell cycle dependent. We used a serum-starved human foreskin fibroblast model to determine changes in COX-2 mRNA, protein, and promoter activity in response to stimulation with interleukin-1b (IL-1b) and phorbol 12-myristate 13-acetate (PMA) at G0, G1, S and G2/M phases of the cell cycle. IL-1b (1 ng/ml) and PMA (100 nM) induced robust COX-2 expression in the G0 cells, and the level of COX-2 expression declined progressively after the cells had entered the cell cycle.

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate.

The pharmacological action of salicylate cannot be explained by its inhibition of cyclooxygenase (COX) activity. In this report, the effects of aspirin and sodium salicylate on COX-2 expressions in human umbilical vein endothelial cells and foreskin fibroblasts were evaluated. Aspirin and sodium salicylate at therapeutic concentrations equipotently blocked COX-2 mRNA and protein levels induced by interleukin-1beta and phorbol 12-myristate 13-acetate.

Identification of thromboxane A2 synthase active site residues by molecular modeling-guided site-directed mutagenesis.

Human thromboxane A2 synthase (TXAS) exhibits spectral characteristics of cytochrome P450 but lacks monooxygenase activity. Its distinctive amino acid sequence makes TXAS the sole member of family 5 in the P450 superfamily. To better understand the structure-function relationship of this unusual P450, we have recently constructed a three-dimensional model for TXAS using P450BM-3 as the template (Ruan, K.

Bleeding disorder due to platelet prostaglandin H synthase-1 (PGHS-1) deficiency.

Defective platelet prostaglandin H synthase (PGHS) activity has been recognized as a cause of bleeding disorders, but the defect has not been characterized. We evaluated three female patients aged 37, 48 and 55 who presented with a mild bleeding disorder due to platelet dysfunction. None of the patients had underlying diseases or reported use of aspirin or other nonsteroidal anti-inflammatory drugs.

Differential expression of thromboxane A synthase and prostaglandin H synthase in megakaryocytic cell line.

We determined the expression of isoforms of prostaglandin H synthase (PGHS) and thromboxane A synthase (TXAS) in a human megakaryocyte cell line (MEG-01. The basal levels of full-length TXAS mRNA and the 60 kDa TXAS protein were high when compared to those of PGHS-1 and PGHS-2 in uninduced cells. Despite a high TXAS level, uninduced MEG-01 cells synthesized only a small amount of thromboxane A2 (TXA2) due to limited PGHS-1 or PGHS-2 expressions.

Kinetics of prostacyclin synthesis in PGHS-1-overexpressed endothelial cells.

The availability of a human endothelial cell overexpressed with prostaglandin H synthase-1 (PGHS-1) by retrovirus-mediated gene transfer made it possible to quantify the kinetics of prostacyclin [prostaglandin (PG)I2] synthesis and PGHS-1 turnover. Prostacyclin synthesis in response to arachidonate (AA) and ionophore A-23187 fit a single exponential kinetics. The rate constants for AA- and ionophore-treated cells were 0.

[Antiphospholipid sydrome--recurrent thrombosis and foetal loss due to antiphospholipid antibodies].

A 36-year old woman with recurrent thrombosis manifested in the form of venous thrombosis of the leg, thrombus in the right atrium and ventricle of the heart, pulmonary embolism and recurrent foetal loss, is described. Laboratory results showed prolonged APTT and normal coagulation factors. All this suggested to lupus anticoagulant (LA), which was confirmed by prolonged KCT, DRVVT, false positive VDRL test, and high level of anticardiolipin antibodies (ELISA).