Cilostazol inhibits cytokine-induced nuclear factor- B activation via AMP-activated protein kinase activation in vascular endothelial cells

Hattori, Yoshiyuki; Suzuki, Kunihiro; Tomizawa, Atsuko; Hirama, Noriko; Okayasu, Toshie; Hattori, Sachiko; Satoh, Hiroaki; Akimoto, Kazumi; Kasai, Kikuo

doi:10.1093/cvr/cvn226

Cited by 56 publications

(47 citation statements)

References 24 publications

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“…Otsuki et al 8) reported that cilostazol repressed vascular cell adhesion molecule-1 gene transcription in cultured HUVEC by inhibiting NF-B binding to its recognition sequence. Recently, Hattori et al 25) documented that cilostazol inhibited cytokine-induced NF-B activation via AMP-activated protein kinase activation in HUVEC; however, our results indicated that cilostazol failed to affect the cytokine-induced accumulation of STAT1 and NF-B in HUVEC nuclei.…”

Section: Discussioncontrasting

confidence: 87%

Cilostazol Inhibits Cytokine-Induced Tetrahydrobiopterin Biosynthesis in Human Umbilical Vein Endothelial Cells

Shiraishi

Ikemoto

Tada

et al. 2011

JAT

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Aims: Cilostazol, a type phosphodiesterase inhibitor, is utilized for the treatment of intermittent claudication and is considered to have the beneficial effects against the atherogenic process. In the present study, we examined the effects of cilostazol on BH4 biosynthesis in HUVEC treated with a mixture of the pro-inflammatory cytokines IFN-and TNF-. Methods: Isolated HUVECs were grown to confluence and treated with IFN-(300 units/mL) and TNF-(300 units/mL) for 16 h in order to stimulate BH4 biosynthesis. The BH4 levels were measured by HPLC. The mRNA expression of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH4 biosynthesis, and GTPCH feedback regulatory protein (GFRP) were quantified by real-time PCR. The GTPCH protein expression was assessed by western blot analysis. Results: Cilostazol significantly reduced the BH4 levels in cytokine-stimulated HUVEC. Cilostazol produced a concomitant increase in the cAMP levels in HUVEC. Cilostazol decreased the GTPCH activity as well as the expression of GTPCH mRNA and protein. 8-bromo-cAMP (8Br-cAMP), a cell-permeable cAMP analogue, did not reproduce the effects of cilostazol. Cilostazol did not affect the cytokine-induced inhibition of GFRP mRNA expression. Conclusions: We conclude that cilostazol inhibited cytokine-stimulated BH4 biosynthesis via a cAMP-independent mechanism in HUVEC. Our data indicate that cilostazol reduced GTPCH activity and did so by suppressing the GTPCH protein levels. J Atheroscler Thromb, 2011; 18:312-317.

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Section: Discussioncontrasting

confidence: 87%

Cilostazol Inhibits Cytokine-Induced Tetrahydrobiopterin Biosynthesis in Human Umbilical Vein Endothelial Cells

Shiraishi

Ikemoto

Tada

et al. 2011

JAT

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“…20 Therefore, cilostazol not only inhibits platelet aggregation 20 but also has favorable pleiotropic effects on the diverse processes in preclinical studies. [22][23][24] Adjunctive cilostazol can reduce aspirin and clopidogrel resistance in patients with vascular disease 18,19,43 Cilostazol not only can inhibit oxidative stress and inflammatory burden 23,44 but also can protect from endothelial senescence and dysfunction. 22,24 Enhancement of endothelial nitric oxide synthase by cilostazol underlies its vasodilating property, 22 which is used for intermittent claudication and cerebral infarction.…”

Section: Discussionmentioning

confidence: 99%

“…20 Unlike other antiplatelet agents, cilostazol not only inhibits platelet aggregation 20 but also has favorable pleiotropic effects on neointimal hyperplasia after PCI 21 and the diverse processes of atherosclerosis. [22][23][24] Furthermore, cilostazol is mainly converted into the active metabolites by the CYP3A system, 25 which might imply less impact of the CYP2C19 mutant allele for additive platelet inhibition with cilostazol.…”

Section: Clinical Perspective On P 459mentioning

confidence: 99%

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Hwang

Jeong²,

Kim³

et al. 2010

Circ: Cardiovascular Interventions

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Background-Among patients treated with clopidogrel, carriers of the cytochrome P450 (CYP) 2C19 loss-of-function allele have shown increased platelet reactivity and higher rates of ischemic events. Although adjunctive cilostazol to dual antiplatelet therapy (or "triple antiplatelet therapy") intensifies platelet inhibition, it remains unknown whether triple antiplatelet therapy after percutaneous coronary intervention can achieve adequate platelet inhibition in patients with the CYP2C19 mutant allele. Methods and Results-CYP2C19 genotyping for *1, *2, and *3 was performed in 134 high-risk patients undergoing elective percutaneous coronary intervention. After measurement of preprocedural platelet reactivity, patients were randomly assigned to receive either adjunctive cilostazol 100 mg twice daily (triple group; nϭ69) or high maintenance-dose (MD) clopidogrel of 150 mg daily (high-MD group; nϭ65). Using light transmittance aggregometry and the VerifyNow P2Y 12 assay, platelet reactivity was assessed before the index procedure and at 30-day follow-up. The primary end point was absolute change in maximal platelet aggregation (⌬Agg max ) according to CYP2C19 genotyping. High posttreatment platelet reactivity was defined as 5 mol/L ADP-induced maximal platelet aggregation Ͼ50%.

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“…It has even been proposed that the vascular consequences of the hypo-adiponectinemia associated with atherosclerosis and diabetes may be circumvented by agents that increase AMPK activity. 150 A number of compounds are reported to activate the AMPK in endothelial cells and improve endothelium-dependent relaxation, including the selective inhibitor of phosphodiesterase 3 cilostazol, 65,151 fenofibrate, 64,152,153 and rosiglitazone. 28 Polyphenols such as resveratrol also increase phosphorylation of AMPK 154 and improve the survival of mice on a high-calorie diet.…”

Section: Fisslthaler and Fleming Ampk In Endothelial Signaling 121mentioning

confidence: 99%

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

Fißlthaler

Fleming

2009

Circulation Research

276

283

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Abstract-The AMP-activated protein kinase (AMPK) was initially identified as the kinase that phosphorylates the 3-hydroxy 3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme for cholesterol biosynthesis. As the name suggests, the AMPK is activated by increased intracellular concentrations of AMP, and is generally described as a "metabolite-sensing kinase" and when activated initiates steps to conserve cellular energy. Although there is a strong link between the activity of the AMPK and metabolic control in muscle cells, the activity of the AMPK in endothelial cells can be regulated by stimuli that affect cellular ATP levels, such as hypoxia as well as by fluid shear stress, Ca 2ϩ -elevating agonists, and hormones such as adiponectin. To date the AMPK in endothelial cells has been implicated in the regulation of fatty acid oxidation, small G protein activity and nitric oxide production as well as inflammation and angiogenesis. Moreover, there is evidence indicating that the activation of the AMPK may help to prevent the vascular complications associated with the metabolic syndrome. Key Words: angiogenesis Ⅲ nitric oxide synthase Ⅲ atherosclerosis Ⅲ 3-hydroxy-3-methylglutaryl coenzyme A Ⅲ energy metabolism T he AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine protein kinase consisting of the catalytic subunit (␣) and 2 regulatory subunits (␤ and ␥) that exist as multiple isoforms and splice variants, resulting in the generation of 12 possible heterotrimeric combinations. As its name suggests, the AMPK is activated in many different cell types by increased intracellular concentrations of AMP and is generally referred to as a "metabolite-sensing kinase." Indeed, the AMPK is activated following heat shock, vigorous exercise, hypoxia/ischemia, and starvation and appears to be a metabolic master switch, phosphorylating key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, skeletal muscle fatty acid oxidation, and protein synthesis (reviewed recently 1,2 ). Although the complex picture regarding the regulation of AMPK activity is far from complete, it seems safe to state that the AMPK determines whole body insulin sensitivity and may prevent insulin resistance, in part, by inhibiting pathways that antagonize insulin signaling. Through its effects on signaling, metabolism, and gene expression, the AMPK enhances insulin sensitivity and may reduce the risk of type 2 diabetes. 3 The 2 previous review articles in this series have focused on the role of the AMPK in metabolic control and insulin signaling 4 and in the heart. 5 This review focuses on the role of the AMPK in vascular cells and the data implicating defects in AMPK signaling in the development of vascular disease. Activation of the AMPKEach subunit within the heterotrimeric AMPK complex has a distinct structure and function and their interaction is necessary for the modulation of kinase activity. The ␣ subunits Ori...

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Cilostazol inhibits cytokine-induced nuclear factor- B activation via AMP-activated protein kinase activation in vascular endothelial cells

Abstract: In the light of these findings, we suggest that cilostazol might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-kappaB following AMPK activation.

Cited by 56 publications

References 24 publications

Cilostazol Inhibits Cytokine-Induced Tetrahydrobiopterin Biosynthesis in Human Umbilical Vein Endothelial Cells

Cilostazol Inhibits Cytokine-Induced Tetrahydrobiopterin Biosynthesis in Human Umbilical Vein Endothelial Cells

Cytochrome 2C19 Polymorphism and Response to Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention

Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells

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