These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.

When a mouse osteoblastic cell line MC3T3-E1 was cultured in the presence of tumor necrosis factor ␣ (TNF␣), the release of prostaglandin E 2 and the cyclooxygenase activity increased in a dose-and time-dependent manner. The increase of the enzyme activity was attributed mostly to the induction of cyclooxygenase-2 rather than cyclooxygenase-1 as judged by the inhibitory effect of NS398, Western blotting, and Northern blotting. In this system we attempted to elucidate the transcriptional regulation of the cyclooxygenase-2 gene. As examined by the luciferase assay, two positive regulatory regions (؊186 to ؊131 and ؊512 to ؊385 base pairs) were found in the 5-flanking promoter region of the mouse cyclooxygenase-2 gene in the TNF␣-stimulated cells. The former included putative NF-IL6 (C/ EBP␤) and AP2 elements, and the latter contained the NFB motif. A DNA probe including the NF-IL6 and AP2 sites gave positive bands upon electrophoretic mobility shift assay using the nuclear extracts of MC3T3-E1 cells. The bands were supershifted by the addition of anti-NF-IL6 antibody but not by anti-AP2 antibody. A probe including the NFB site also gave positive bands, which were supershifted by anti-NFB p50 and p65 antibodies. Furthermore, when the motif of NF-IL6 or NFB or both was subjected to point mutation, the luciferase activity was markedly reduced. These data suggested a potential role of both NF-IL6 and NFB in the induction of cyclooxygenase-2 by TNF␣.

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PLA2G2D ameliorates skin inflammation through mobilizing pro-resolving lipid mediators.

Summary Metabolic disorders including obesity and insulin resistance have their basis in dysregulated lipid metabolism and low-grade inflammation. In a microarray search of unique lipase-related genes whose expressions are associated with obesity, we found that two secreted phospholipase A2s (sPLA2s), PLA2G5 and PLA2G2E, were robustly induced in adipocytes of obese mice. Analyses of Pla2g5−/− and Pla2g2e−/− mice revealed distinct and previously unrecognized roles of these sPLA2s in diet-induced obesity. PLA2G5 hydrolyzed phosphatidylcholine in fat-overladen low-density lipoprotein to release unsaturated fatty acids, which prevented palmitate-induced M1 macrophage polarization. As such, PLA2G5 tipped the immune balance toward an M2 state, thereby counteracting adipose tissue inflammation, insulin resistance, hyperlipidemia and obesiy. PLA2G2E altered minor lipoprotein phospholipids, phosphatidylserine and phosphatidylethanolamine, and moderately facilitated lipid accumulation in adipose tissue and liver. Collectively, the identification of “metabolic sPLA2s” adds this gene family to a growing list of lipolytic enzymes that act as metabolic coordinators.

More than one third of the phospholipase A 2 (PLA 2 ) enzymes belong to the secreted PLA 2 (sPLA 2 ) family, which contains 10 catalytically active isoforms (IB, IIA, IIC, IID, IIE, IIF, III, V, X, and XIIA) and one inactive isoform (XIIB) in mammals ( 1-4 ). Individual sPLA 2 s exhibit unique tissue and cellular distributions and substrate selectivity, suggesting their distinct biological roles. Because sPLA 2 s are secreted and require millimolar Ca 2+ for their catalytic action, they principally target phospholipids in the extracellular space. Individual sPLA 2 s participate in diverse biological This work was supported by

Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells, and acts as a survival factor against endothelial cell death. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. We have previously reported that intraarterial administration of recombinant HGF induced angiogenesis in a rabbit hindlimb ischemia model. In this study, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease rather than recombinant therapy, due to its disadvantages. Initially, we examined the transfection of 'naked' human HGF plasmid into a rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid resulted in a significant increase in blood flow as assessed by laser Doppler imaging, accompanied by the detection of human HGF protein. A significant increase in capillary density was found in rats transfected with human HGF as compared with control vector, in a dose-dependent manner (P Ͻ 0.01). Importantly, at 5 weeks after transfection, the degree of angiogenesis induced by transfection of HGF plasmid was significantly greater than that caused by

Phospholipase A(2) (PLA(2)) catalyses the hydrolysis of the sn-2 position of glycerophospholipids to yield fatty acids and lysophospholipids. So far, more than 30 enzymes that possess PLA(2) or related activity have been identified in mammals. About one third of these enzymes belong to the secreted PLA(2) (sPLA(2)) family, which comprises low molecular weight, Ca(2+) requiring, secreted enzymes with a His/Asp catalytic dyad. Individual sPLA(2)s display distinct localizations and enzymatic properties, suggesting their specialized biological roles. However, in contrast to intracellular PLA(2)s, whose roles in signal transduction and membrane homoeostasis have been well documented, the biological roles of sPLA(2)s in vivo have remained obscure until recently. Over the past decade, information fuelled by studies employing knockout and transgenic mice as well as specific inhibitors, in combination with lipidomics, has clarified when and where the different sPLA(2) isoforms are expressed, which isoforms are involved in what types of pathophysiology, and how they exhibit their specific functions. In this review, we highlight recent advances in PLA(2) research, focusing mainly on the physiological functions of sPLA(2)s and their modes of action on 'extracellular' phospholipid targets versus lipid mediator production.