Previous studies in this laboratory established that low density lipoprotein (LDL) incubated with cultured endothelial cells, smooth muscle cells, or macrophages undergoes a free radical-catalyzed oxidative modification that generates lipid peroxides and extensive structural changes in the LDL molecule. The oxidatively modified LDL strongly inhibited chemotactic responses of the mouse resident peritoneal macrophage. The present studies show that this oxidized LDL does not inhibit the motility of mouse monocytes and actually exhibits a chemotactic activity for human monocytes; the chemotactic activity of the oxidized LDL resides in the lipid fraction. These findings allow us to propose a pathogenetic sequence by which elevated plasma LDL levels, followed by oxidative modification in the arterial wall, could sufficiently account for the generation of the lipid-laden foam cells and the initiation of the fatty streak, the earliest well-defined lesion in atherogenesis.Accumulation of lipid in the arterial intima is central to the development of atherosclerosis. Intimal lipid accumulates intracytoplasmically in foam cells, which are derived both from medial smooth muscle cells (1, 2) and monocyte-derived macrophages (3)(4)(5), the latter probably being quantitatively more important (3-5). Exactly how monocytes are recruited and retained in the artery wall remains unclear, but probably the initial event is adhesion to the endothelial surface (3) followed by penetration that is influenced by a chemotactic factor(s). Many different factors chemotactic for monocytes have been described (6); the relative importance of these remains uncertain. Crude extracts of whole aorta contain chemotactic activity (7), and cultured arterial smooth muscle cells and macrophages release chemotactic activity into the culture medium (8). We recently described release of chemotactic activity for mouse resident peritoneal macrophages from cultured aortic endothelial cells (9) and showed that oxidatively modified low density lipoprotein (LDL) inhibited the chemotactic response of the macrophage. In the present studies we confirm the finding of Berliner et al. (10) that endothelial cell-conditioned medium is chemotactic also for human monocytes. However, oxidatively modified LDL, instead of inhibiting the motility of monocytes actually enhances their motility. We further show that the chemotactic activity resides in the lipid fraction of the modified LDL, presumably in one or another peroxidized lipid component. Thus oxidative modification of LDL, in addition to favoring the accumulation of cholesterol stores in developing foam cells (11), could play a role in recruitment and retention of monocyte/macrophages into the subendothelial space and, finally, may contribute to atherogenesis through injury to endothelial cells. MATERIALS AND METHODSHam's F-10 medium and fetal bovine serum were from HyClone (Logan, UT); female Swiss Webster mice were from Simonsen Laboratories (Gilroy, CA); Ficoll/Hypaque, bovine serum albumin, zymosan A, fucoidi...

Native low density lipoprotein (LDL) does not affect monocyte/macrophage motility. On the other hand, oxidatively modified LDL inhibits the motility of resident peritoneal macrophages yet acts as a chemotactic factor for circulating human monocytes. We now show that lysophosphatidylcholine (lyso-PtdCho), which is generated by a phospholipase A2 activity during LDL oxidation, is a potent chemotactic factor for monocytes. It is not chemotactic for neutrophils or for resident macrophages. Platelet-activating factor, after treatment with phospholipase A2, becomes chemotactic for monocytes, whereas the intact factor is not. Synthetic 1-palmitoyl-lyso-PtdCho showed chemotactic activity comparable to that of the lyso-PtdCho fraction derived from oxidized LDL. The results suggest that Iyso-PtdCho in oxidized LDL may favor recruitment of monocytes into the arterial wall during the early stages of atherogenesis. Generation of lyso-PtdCho, either from LDL itself or from membrane phospholipids of damaged cells, could play a more general role in inflammatory processes throughout the body.One of the characteristics of the earliest atherosclerotic lesion is the intimal accumulation of lipid-laden foam cells derived predominantly from monocyte/macrophages (1-5).Exactly how these cells are recruited and retained in the artery wall remains unclear, but it seems likely that adhesion molecules and chemotactic factors are involved. Although many different chemotactic factors for monocytes have been described (6-9), their relative importance in relation to atherogenesis remains to be determined. The possibility that a high plasma level of low density lipoprotein (LDL) might play a role in monocyte recruitment seemed attractive in view of the fact that a high LDL level is the proximate consequence of LDL receptor deficiency in homozygous familial hypercholesterolemia and, therefore, must somehow account for the genesis of the fatty streak lesions (10

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Abstract-The purpose of this study was to determine whether superoxide anion is produced endogenously in the rat aortic adventitia and whether sufficient superoxide anion is produced to interfere with the response of the rat aorta to nitric oxide. Relaxation was measured in rings of the rat thoracic aorta, which were oriented so that the adventitial or luminal surface could be preferentially exposed to nitric oxide or sodium nitroprusside. To accomplish this, the rings were mounted (1) with the adventitia facing outward, (2) with the adventitia facing inward after inverting, or (3) with the adventitia facing outward after inverting twice (to control for the inverting procedure). The relaxation to nitric oxide, but not to sodium nitroprusside, was less in rings with the adventitia facing outward compared with those in which it faced inward. In contrast, the response to nitric oxide via either surface was similar when extracellular superoxide anion was scavenged with superoxide dismutase. Incubation of rings with nitro blue tetrazolium (NBT) resulted in blue formazan staining of the adventitia, and lucigenin chemiluminescence was significantly greater when detected from the adventitial compared with the intimal aspect of the artery. The reduction of NBT in intact aortic rings was 30Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and was significantly decreased by superoxide dismutase to 19Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and by a synthetic superoxide dismutase mimic, Euk-8, to 11Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1. The NADPH oxidase inhibitor, diphenyleneiodonium, decreased NBT reduction to 9Ϯ1 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1, whereas inhibitors of xanthine oxidase, mitochondrial oxidases, and nitric oxide synthase were ineffective. Immunohistochemical staining indicated the localization of NADPH oxidase proteins gp91 phox , p22 phox , p47 phox , and p67 phox almost exclusively in the adventitia of the rat aorta with no substantial staining in the media. These results indicate that NADPH oxidase located in the adventitia of rat thoracic aorta generates sufficient extracellular superoxide anion to constitute a barrier capable of inactivating nitric oxide. This study suggests that adventitial superoxide anion can play a role in the pathophysiology of the arterial wall. (Circ Res. 1998;82:810-818.)