Prostaglandin H2 (PGH2 [endoperoxide]) is an immediate product of prostaglandin H (PGH) synthase activity (cyclooxygenase) and a likely candidate to mediate endothelium-dependent contractions evoked by acetylcholine in the aorta of the spontaneously hypertensive rat (SHR). Experiments were designed to investigate whether or not endothelium-dependent contractions were associated with an increased expression of PGH synthase, an augmented acetylcholine-induced release of PGH2, and/or a hypersensitivity of the smooth muscle to endoperoxides in SHR aorta compared with normotensive Wistar-Kyoto (WKY) aorta. In SHR aorta, endothelium-dependent contractions to acetylcholine were abolished by tenidap (10(-8) mol/L), a preferential PGH synthase-1 inhibitor, but slightly impaired by NS-398 (10(-6) mol/L), a preferential PGH synthase-2 inhibitor. PGH synthase-1 expression, which was evaluated by both reverse transcriptase-polymerase chain reaction and Western blotting, was about twofold greater in preparations with endothelium from SHR than from WKY rats. There was no difference in PGH synthase-1 expression between preparations with and those without endothelium in both strains. In SHR but not WKY aortas, acetylcholine (10(-5) mol/L, 5 minutes) caused a significant endothelium-dependent release of PGH2 as measured by gas chromatography/mass spectrometry. PGH2 evoked more potent contractions in rings without endothelium from SHR than from WKY rats, whereas the thromboxane analogue U46619 and prostaglandin F2 alpha caused a comparable response in both preparations. These results show that endothelium-dependent contractions to acetylcholine in SHR aorta are associated with a greater expression of PGH synthase-1, a significant release of PGH2, and a hypersensitivity of the smooth muscle to the endoperoxide.

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Stimulation of thymidine incorporation by basic fibroblast growth factor or epidermal growth factor treatment of cultured quiescent smooth muscle cells (rat and human) was attenuated by the concomitant treatment with interleukin-1 beta in the presence of indomethacin. Platelet-derived growth factor-AB and -BB-induced thymidine incorporation was not inhibited by the presence of the cytokine under similar experimental conditions. Elevation of nitrite levels in the conditioned medium of cultures exposed to interleukin-1 beta correlated with the inhibition of thymidine incorporation. Platelet-derived growth factor-AB and -BB inhibited the production of nitric oxide (measured as nitrite levels in conditioned medium) by cells treated simultaneously with interleukin-1 beta and growth factor. However, platelet-derived growth factor-AA neither affected nitrite production nor thymidine incorporation by smooth muscle cells. Levels of cytokine-stimulated nitrite production by smooth muscle cells were increased synergistically by the presence of fibroblast growth factors or epidermal growth factor. The inhibition of thymidine incorporation and concomitant elevation of nitrite production was abolished in the presence of nitro-L-arginine. Cultures maintained in the presence of low levels of the cytokine for 9 days were growth-inhibited, and this was reversed when culture medium was supplemented with nitro-L-arginine. The treatment of smooth muscle cells, which were grown in coculture inserts with the cytokine to induce nitric oxide production, before their combination with other quiescent layers of cells resulted in the inhibition of thymidine incorporation by this second layer of cells regardless of the growth factor used for stimulation. Nitric oxide may act as an endogenous inhibitor of smooth muscle cell proliferation in the vessel wall, and impairment of its production may be one action of potent vascular mitogens such as platelet-derived growth factor.

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What ' s known on the subject? and What does the study add? Pervasive infl ammatory infi ltrates, mainly composed of chronically activated T cells and monocytes/macrophages, have been observed in benign prostatic hyperplasia (BPH). Permixon ® , a hexanic lipidosterolic extract of Serenoa repens (hexanic LSESr) used to treat urinary dysfunction in BPH patients, has anti-infl ammatory activities. This paper provides new insights into the anti-infl ammatory properties of Permixon ® . We report that hexanic LSESr inhibits early steps of leukocyte infi ltration in vitro by downregulating MCP-1/CCL2 and VCAM-1 expression.

SUMMARY1. Experiments were performed to investigate the effects of human recombinant interleukin-1,8 on the production of vasoactive substances by human aortic smooth muscle cells in culture. Smooth muscle cells were cultured either on microcarrier beads for bioassay experiments, or in multiwell plates for the determination of nitrite levels. 5. These data demonstrate that the inflammatory and immunological mediator interleukin-1 can stimulate the production of a nitric oxide-like substances) in cultured human smooth muscle cells leading to the activation of soluble guanylate cyclase. Liberation of transforming growth factor-,8 by activated platelets may inhibit these reactions.MS 960)0

Peroxisome proliferator-activated receptors (PPARs) regulate storage and catabolism of fats and carbohydrates. PPAR␥ activity increases insulin sensitivity and adipocyte differentiation at the expense of adipogenesis and weight gain. The goal of this study was to 1) clone the promoter of the human adipocyte fatty acid binding protein (aP2) gene, namely fatty acid-binding protein-4, 2) characterize its pharmacological regulation, and 3) determine its putative predictability for adipogenesis. Among the selected PPAR agonists, rosiglitazone and pioglitazone displayed the highest maximal efficacy (E max ) on reporter-gene assays in COS-7 cells cotransfected by either a galactosidase 4-response elementbased or a human aP2 promoter-based Luc reporter vector, along with either chimeric or full-length human PPAR expression plas- -0072), and indomethacin behaved as partial agonists relative to pioglitazone in full-length human aP2-PPAR␥2. Beyond their partial PPAR␥ agonist properties, these compounds elicited a lower maximal up-regulation of mouse aP2 mRNA in 3T3-L1 adipocytes as compared with pioglitazone; these properties paralleled a time-dependent increase in neutral lipids. By contrast, the selective PPAR␣ agonist 2,2-dichloro-12-(4-chlorophenyl)dodecanoic acid (BM-17.0744) neither stimulated the human aP2-PPAR␣ promoter reporter-gene assay, thus demonstrating a specific interaction between PPAR␥ and the aP2 promoter, nor affected lipogenesis in 3T3-L1 cells. Altogether, these data characterized a functional promoter of the human aP2 gene; its in vitro pharmacological regulation in PPAR␥-mediated reporter-gene assay may represent an interesting complement or an alternative to time-consuming procedures aiming at discriminating PPAR ligands with low lipogenic properties.Metabolic syndrome is characterized by the clustering of at least three risk factors among hypertension, certain types of dyslipidemia, impaired glucose tolerance and type II diabetes, and obesity. These metabolic abnormalities lead to atherosclerosis and related complications (Haffner and Taegtmeyer, 2003). The control of lipid and carbohydrate metabolism, including physiologic and pharmacological treatments, represents a valid rationale to reduce cardiovascular diseases in patients with metabolic syndrome (Beckman et al., 2003;Wilson and Grundy, 2003).PPARs are a subclass of the nuclear receptor superfamily acting as ligand-dependent transcription factors (Kersten et al., 2000). Three subtypes were identified; the ␣ isoform is the primary subtype expressed in liver, but also in heart and kidney, and acts as a major regulator of metabolism of fats, catabolism of fatty acids, and synthesis and catabolism of lipoproteins (Barbier et al., 2002). PPAR␣ is also involved in Parts of this work were presented as a poster at the 74th Congress of the European Atherosclerosis Society (April 17-20, 2004, Seville, Spain).Article, publication date, and citation information can be found at