[...]... Linoleic Acid 15-LOX-1 15-LOX-2 12-S-LOX 12-R-LOX 8-LOX 5-LOX 5-S-HETE 13-S-HODE 15-S-HETE Decreased cell proliferation, increased differentiation, promotion of apoptosis, attenuation of inflammatory response Figure 3 12-S-HETE 12-R-HETE 8-S-HETE LTB4 Increased cell proliferation, promotion of tissue angiogenesis, suppression of tumor apoptosis, chemoattraction of inflammatory cells and potentiation... metabolism (see color insert) promote angiogenesis The 15-LOX isoenzymes (15-LOX1, 15-LOX-2) convert arachidonic acid to 15-S-HETE and linoleic acid to 13-S-hydroxy-9,11-octadecadienoic acid (13-S-HODE) These substances may have effects opposite to those of the 5-, 8-, and 12-LOX, as they induce epithelial cell differentiation and promote both growth inhibition and cell apoptosis Leukotrienes are a family of... are derived from platelets (12-S-LOX), epidermis (12-R-LOX and 15-LOX-2), or reticulocytes (12-LOX-1) The physiologic effects of lipoxygenase metabolites have not been characterized as extensively as those produced by cyclooxygenase activity The 5-, 8-, and 12-LOX isoforms result in production of hydroxyeicosatetraenoic acids (HETEs), including 5-S-HETE, LTB4, 8-S-HETE, and 12HETE (Figure 3) In general,... of CXC chemokines, and TNF-induced oxidized LDL receptor (LOX-1) and induces stress proteins including heme oxygenase and plasminogen activator inhibitor type-1 (PAI-1) in a number of ECs (including brain microvascular) 15d-PGJ2 also signals in a PPAR-independent manner in ECs, inducing apoptosis and synthesis of GSH and IL-8 Figure 3 In addition to 15d-PGJ2, additional prostaglandins that signal in... factor; 15d-PGJ2, 15-deoxy-d (12,14)-prostaglandin J2; PAI-1, plasminogen activator inhibitor type-1 (see color insert) 72 4 PART III Pathology challenged mice This suggests 5-LOX may be upregulated in inflammatory-activated endothelium, although the mechanisms involved are unknown Finally, although functional 5-LOX protein is not expressed in ECs, leukotrienes can be generated by HUVECs and pig aortic ECs... Acknowledgments Research funding from the Wellcome Trust and British Heart Foundation is gratefully acknowledged Bibliography PROSTAGLANDIN H SYNTHASE Belton, O., Byrne, D., Kearney, D., Leahy, A., and Fitzgerald, D J (2000) Cyclooxygenase-1 and -2 -dependent prostacyclin formation in patients with atherosclerosis Circulation 102, 840–845 This study describes the relative importance of PGHS-1 and -2 in generation... Caughey, G E., Cleland, L G., Penglis, P S., Gamble, J R., and James, M J (2001) Roles of cyclooxygenase (COX )-1 and COX-2 in prostanoid production by human endothelial cells: Selective upregulation of prostacyclin synthesis by COX-2 J Immunol 1 67, 2831–2838 Smith, W L., and Marnett, L J (1991) Prostaglandin endoperoxide synthase: Structure and catalysis Biochim Biophys Acta 1083, 1– 17 This is an excellent... superoxide and related ROS triggers alterations in the expression of genes encoding proteins that control the tissue inflammatory responses, such as endothelial adhesion molecules (intracellular adhesion molecule-1 (ICAM-1), and P- and E-selectins) as well as superoxide dismutase, NO synthase and heme oxygenase-1 Nitric oxide depression is by itself a pro-inflammatory stimulator (Kubes et al., 1991) and a... 2) Prostaglandin H Synthases-1 and -2 in ECs Enzymology of PGHS-1 and -2 Prostaglandins (PGs) are predominantly generated through the action of PGHS, of which there are both consti- 72 1 Copyright © 2006, Elsevier Science (USA) All rights reserved 72 2 PART III Pathology Figure 1 Generation of bioactive eicosanoids by healthy and inflammatory-activated endothelium Following its hydrolysis from the membrane... regarding function and control of these pathways in ECs (especially PGHS and LOX), others, especially the CYP enzymes, are less studied Studying the biological roles and signaling pathways of CYP in EC is becoming a major focus of research in vascular biology and will undoubtedly lead to a fuller understanding of their roles in both normal homeostasis and vascular pathophysiology 72 6 PART III Pathology Finally, . adhesion molecule-1 (ICAM-1), and P- and E-selectins) as well as superoxide dismutase, NO synthase and heme oxygenase-1. Nitric oxide depression is by itself a pro-inflammatory stim- ulator (Kubes. via mem- brane depolarization. Several types of voltage-sensitive ion channels, including L-type Ca 2+ (Ca L ) channels, voltage-gated K + (K V ) chan- nels, and high-conductance voltage- and Ca 2+ -sensitive. Venule Baseline Hypercholesterolemia IL-12 IFN- g NAD(P)H ox O 2 - NAD(P)H ox ICAM-1 L-arg NO eNOS NO L-arg NO eNOS NO H 2 O 2 H 2 O Cat CuZn-SOD O 2 - NAD(P)Hox Monocyte Platelet Neutrophil Lymphocyte Endothelial