Cilostazol inhibits high glucose-mediated endothelial-neutrophil adhesion by decreasing adhesion molecule expression via NO production

Omi, Hitoshi; Okayama, Naotsuka; Shimizu, Manabu; Fukutomi, Tatsuya; Nakamura, Atsushi; Imaeda, Kazuo; Okouchi, Masahiro; Itoh, Makoto

doi:10.1016/j.mvr.2004.05.002

Cited by 71 publications

(46 citation statements)

References 42 publications

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“…14) In addition, Cilostazol inhibits endothelial-neutrophil adhesion by decreasing adhesion molecule expression via NO production, and leukocyte integrin mac, leading to a potential reduction in restenosis after coronary stent implantation. 15) Further, it has been reported that MT can prevent kainic acid-induced hippocampus damage 16) ; therefore, it is noteworthy that Cilostazol induced MT protein in cultured HBMEC.…”

Section: Discussionmentioning

confidence: 98%

Induction of Metallothionein Synthesis by Cilostazol in Mice and in Human Cultured Neuronal Cell Lines

Suzuki

Masui

Ohnuki

et al. 2007

Biological & Pharmaceutical Bulletin

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Cilostazol, a quinolinone derivative, is approved by the Food and Drug Administration for the treatment of intermittent claudication.1) It has been shown that Cilostazol has an inhibitory effect on platelet aggregation and thronbosis in feline cerebral ischemia.2) Cilostazol has also been shown to significantly reduce the risk of recurrent strokes without affecting the occurrence of intracranial hemorrhage. Recently, the Cilostazol Stroke Prevention Study revealed that Cilostazol reduced the risk of secondary stroke by 41.7% as compared with a placebo 3) suggesting that Cilostazol has a specific effect on small-vessel disease, although the mechanism for this is not well known. It has been shown that Cilostazol and its metabolites reduced the intracellular reactive oxygen species (ROS) induced by LPS in human umbilical vein endothelial cells by directly scavenging hydroxyl radicals. 4)However, the anti-stroke effect of Cilostazol in vivo seems not to be due to its antioxidative effect, because its blood clearance is so rapid, and its concentration in the brain would be too low to directly scavenge ROS. Thus, Cilostazol may cause an anti-stroke effect via the induction of a putative anti-oxidative molecule in the brain.Metallothionein (MT) is a small sulfhydryl-rich protein, the level of which is elevated by various inducers of metals, hormones and cytokines. The induction of MT synthesis has been reported in various tissues, but rarely in the brain. MT is thought to be a multifunctional protein detoxifying heavy metals such as cadmium and inorganic mercury, maintaining zinc and copper homeostasis, and regulating the biosynthesis and activity of zinc-binding proteins such as zinc-dependent transcription factors. MT also has the ability to scavenge ROS. 5,6) Concerning the anti-oxidative activities of MT, a role of MT in neurodegenerative diseases has been proposed.7) Thus, in this experiment, we examined the induction of MT by Cilostazol in the mouse brain and liver, and also in human cultured neuronal cells in order to confirm the possibility that Cilostazol directly induces MT in the human brain as an anti-oxidative effecter molecule. Animals and Treatments Male C57BL/6J mice were purchased from Clea Japan Inc. (Tokyo Japan). They were housed in plastic cages at 23°C with a 12 h light/dark cycle and were given lab food and tap water ad libitum. Mice (7 weeks old) were randomly assigned to treatment groups and were injected i.p. with 0.5% Cilostazol suspended with 0.5% carboxylmethyl cellulose solution or vehicle alone. After various time intervals, the liver and brain were removed from each mouse under anesthetization with sodium pentobarbital and were then stored at Ϫ80°C for the determination of MT level. The mice received humane care throughout the experiments according to the guidelines of Tokushima Bunri University. MATERIALS AND METHODS MaterialsCell Cultures IMR-32 cells, a human neuroblastoma cell line, were obtained from the American Type Culture Collection (ATCC, Rockville, MD, U.S.A.), and maintained ...

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Section: Discussionmentioning

confidence: 98%

Induction of Metallothionein Synthesis by Cilostazol in Mice and in Human Cultured Neuronal Cell Lines

Suzuki

Masui

Ohnuki

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Omi et al (35) described that cilostazol inhibits the expression of adhesion molecules, which promotes a reduction in neutrophil migration. In addition, Shin et al (36) have reported that cilostazol exerts anti-inflammatory effects by reducing superoxide production and inhibiting the release of cytokines, including TNF-a and IL-1, from HUVECs.…”

Section: Discussionmentioning

confidence: 99%

Anti-atherogenic Effects of a New Thienylacylhydrazone Derivative, LASSBio-788, in Rats Fed a Hypercholesterolemic Diet

et al. 2013

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Abstract. The compound LASSBio-788 (N-Allyl (2-thienylidene) 3,4-methylenedioxybenzoylhydrazine) is a thienylacylhydrazone derivative shown to have antiplatelet, vasodilatory, and antiinflammatory properties in vitro. We hypothesize that LASSBio-788 may exert beneficial effects on atherosclerosis. Male wistar rats were divided into 4 groups: Control group received standard rat chow, hypercholesterolemic group (HC) and HC+788 (compound LASSBio-788 group) received hypercholesterolemic diet for 45 days. HC+788 group received compound LASSBio-788 (100 mmol/kg) once daily in the last 15 days. LASSBio-788 reduced the levels of total cholesterol (109.1 ± 4.3 vs. 361.0 ± 12.8 mg/dl), triglycerides (66.1 ± 1.1 vs. 186.9 ± 17.7 mg/dl), LDLc (63.2 ± 6.1 vs. 330.9 ± 9.7 mg/dl), VLDLc (9.8 ± 1.1 vs. 45.0 ± 4.6 mg/dl) and malondialdehyde (4.8 ± 0.3 vs. 9.4 ± 0.5 nmol/ml) compared to the HC group. LASSBio-788 presented antiplatelet properties and decreased inflammatory markers levels. LASSBio-788 promoted a decrease in contractile response to phenylephrine and an improvement in endothelium-dependent vasorelaxant response by increasing two-fold the expression of nitric oxide synthase (eNOS). Our results suggest that the compound LASSBio-788 represents a new multi-targeted drug candidate for the treatment of atherosclerosis.

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“…It also prevents remnant lipoprotein particleinduced monocyte adhesion to endothelial cells by suppressing the expression of adhesion molecules and monocyte chemoattractant protein-1 via a lectin-like receptor for oxidized low-density lipoprotein receptor activation 21) . Furthermore, cilostazol suppresses superoxide production and the expression of adhesion molecules in human endothelial cells via the mediation of cAMP-dependent protein kinase-mediated Maxi-K channel activation 22,23) . In summary, all of these findings show that cilostazol significantly reduces the apoptosis of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Cilostazol on Proliferation of Vascular Smooth Muscle Cells (VSMCs) Through Suppression of the ERK1/2 Pathway

Yoo

Koh

Cho

et al. 2010

JAT

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A Rum Yoo and Seong-Ho Koh contributed equally to this work Aim: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca 2 levels, inhibiting platelet aggregation and inducing vasodilatation. Cilostazol is also known to have an inhibitory effect on the proliferation of VSMCs, but the anti-proliferative mechanism of cilostazol in VSMCs has not yet been established. In the present study, we investigated whether the anti-proliferative mechanism of cilostazol is associated with the suppression of extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways. Methods: To confirm the anti-proliferative effects of cilostazol on VSMCs, VSMCs were induced to proliferate by serum-induced mitogenesis and then were treated with cilostazol for 24 h. And, to investigate whether the anti-proliferative mechanism of cilostazol in VSMCs involves the suppression of the ERK and PI3K pathways, expression of the phosphorylated forms of ERK1/2, Raf, Akt, and glycogen synthase kinase (GSK)-3 were evaluated by western blot. Results: Cilostazol inhibited VSMC proliferation in a dose-dependent manner. Phosphorylated ERK1/2 and Raf were significantly reduced in a dose-dependent manner, whereas phosphorylated Akt and GSK-3 were not changed. Conclusion: These results suggest that suppression of the ERK pathway but not the PI3K pathway is an important mechanism in the anti-proliferative effect of cilostazol on VSMCs.

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Cilostazol inhibits high glucose-mediated endothelial-neutrophil adhesion by decreasing adhesion molecule expression via NO production

Cited by 71 publications

References 42 publications

Induction of Metallothionein Synthesis by Cilostazol in Mice and in Human Cultured Neuronal Cell Lines

Induction of Metallothionein Synthesis by Cilostazol in Mice and in Human Cultured Neuronal Cell Lines

Anti-atherogenic Effects of a New Thienylacylhydrazone Derivative, LASSBio-788, in Rats Fed a Hypercholesterolemic Diet

Inhibitory Effects of Cilostazol on Proliferation of Vascular Smooth Muscle Cells (VSMCs) Through Suppression of the ERK1/2 Pathway

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