Rosuvastatin Suppresses the Inflammatory Responses Through Inhibition of c-Jun N-terminal Kinase and Nuclear Factor-κB in Endothelial Cells

Kim, Yong Sook; Ahn, Young Keun; Hong, Moon Hwa; Kim, Kye Hun; Park, Hyung Wook; Hong, Young Joon; Kim, Ju Han; Kim, Weon; Jeong, Myung Ho; Cho, Jeong Gwan; Park, Jong Chun; Kang, Jung Chaee

doi:10.1097/fjc.0b013e31804a5e34

Cited by 71 publications

(66 citation statements)

References 27 publications

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“…69 -71 These intracellular pathways have also been shown to play a significant role in smooth muscle cells, mast cells, and endothelial cells. [72][73][74] Hence, the expression of PGE 2 -synthesizing enzymes is most likely regulated by a complex network of cytokines and signal transduction pathways, as well as by cross-talk interactions among cells.…”

Section: Discussionmentioning

confidence: 99%

Expression of Prostaglandin E Synthases in Periodontitis

Båge

Kats

Lopez

et al. 2011

The American Journal of Pathology

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The inflammatory mediator prostaglandin E 2 (PGE 2 ) is implicated in the pathogenesis of chronic inflammatory diseases including periodontitis; it is synthesized by cyclooxygenases (COX) and the prostaglandin E synthases mPGES-1, mPGES-2, and cPGES. The distribution of PGES in gingival tissue of patients with periodontitis and the contribution of these enzymes to inflammationinduced PGE 2 synthesis in different cell types was investigated. In gingival biopsies, positive staining for PGES was observed in fibroblasts and endothelial, smooth muscle, epithelial, and immune cells. To further explore the contribution of PGES to inflammation-induced PGE 2 production, in vitro cell culture experiments were performed using fibroblasts and endothelial, smooth muscle, and mast cells. All cell types expressed PGES and COX-2, resulting in basal levels of PGE 2 synthesis. In response to tumor necrosis factor (TNF-␣), IL-1␤, and cocultured lymphocytes, however, mPGES-1 and COX-2 protein expression increased in fibroblasts and smooth muscle cells, accompanied by increased PGE 2 , whereas mPGES-2 and cPGES were unaffected. In endothelial cells, TNF-␣ increased PGE 2 production only via COX-2 expression, whereas in mast cells the cytokines did not affect PGE 2 enzyme expression or PGE 2 production. Furthermore, PGE 2 production was diminished in gingival fibroblasts derived from mPGES-1 knockout mice, compared with wild-type fibroblasts. These results suggest that fibroblasts and smooth muscle cells are important sources of mPGES-1, which may contribute to increased PGE 2 production in the inflammatory condition periodontitis.

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Section: Discussionmentioning

confidence: 99%

Expression of Prostaglandin E Synthases in Periodontitis

Båge

Kats

Lopez

et al. 2011

The American Journal of Pathology

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“…22 In addition, previous studies have shown that TNF-induced expression of cell adhesion molecules was repressed by statins in cultured ECs. [23][24][25] Moreover, we previously showed that KLF4 inhibited TNF-induced expression of VCAM1 through blocking the binding of NF-kB to the VCAM1 promoter in cultured ECs. 11 To clarify the molecular mechanisms whereby statins attenuated renal I/R injury in control mice, but not in Klf4 cKO mice, we examined whether KLF4 contributed to the suppressive effect of statins on TNF-induced VCAM1 expression in HUVECs.…”

Section: Klf4 Mediated the Suppressive Effect Of Statins On Tnf-inducmentioning

confidence: 99%

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

Yoshida

Yamashita

Iwai

et al. 2015

JASN

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Endothelial cells participate in the pathophysiology of ischemic AKI by increasing the expression of cell adhesion molecules and by recruiting inflammatory cells. We previously showed that endothelial Krüppel-like factor 4 (Klf4) regulates vascular cell adhesion molecule 1 (Vcam1) expression and neointimal formation after carotid injury. In this study, we determined whether endothelial Klf4 is involved in ischemic AKI using endothelial Klf4 conditional knockout (Klf4 cKO) mice generated by breeding Tek-Cre mice and Klf4 floxed mice. Klf4 cKO mice were phenotypically normal before surgery. However, after renal ischemia-reperfusion injury, Klf4 cKO mice exhibited elevated serum levels of urea nitrogen and creatinine and aggravated renal histology compared with those of Klf4 floxed controls. Moreover, Klf4 cKO mice exhibited enhanced accumulation of neutrophils and lymphocytes and elevated expression of cell adhesion molecules, including Vcam1 and Icam1, in injured kidneys. Notably, statins ameliorated renal ischemia-reperfusion injury in control mice but not in Klf4 cKO mice. Mechanistic analyses in cultured endothelial cells revealed that statins increased KLF4 expression and that KLF4 mediated the suppressive effect of statins on TNFa-induced VCAM1 expression by reducing NF-kB binding to the VCAM1 promoter. These results provide evidence that endothelial Klf4 is renoprotective and mediates statin-induced protection against ischemic AKI by regulating the expression of cell adhesion molecules and concomitant recruitment of inflammatory cells.

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“…Statins may improve endothelial function by decreasing expression of endothelial adhesion molecules, increasing nitric oxide bioavailability, and attenuating the production of reactive oxygen species. 2,21,22 In addition, statins are thought to stabilize plaque by decreasing lipid oxidation, inflammation, matrix metalloproteinase-2, and cell death and by increasing the content of tissue inhibitor of metalloproteinase-1 and collagen; these effects might reduce distal embolization. 23 Furthermore, statins have been shown to open mitochondrial adenosine triphosphate-sensitive potassium channels, suggesting pharmacological ischemic preconditioning effects.…”

Section: Statins and Myocardial Damagementioning

confidence: 99%

Effects of Pretreatment With Statins on Infarct Size in Patients With Acute Myocardial Infarction Who Receive Fibrinolytic Therapy

Kiyokuni

Kosuge

Ebina

et al. 2009

Circ J

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Circ J 2009; 73: 330 -335 tatins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely used clinically to decrease serum cholesterol levels. 1 Recent studies have focused on the pleiotropic effects of statins, which are independent of their lipid-lowering effects, such as stimulation of fibrinolysis by altering the levels and activities of tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1. 2,3 Statins also reduce hemostasis by inhibiting platelet activation and the procoagulation cascade, and by augmenting the anticoagulation cascade. 4 Thus, statins appear to effectively enhance the fibrinolytic activity of t-PA. An experimental study in animals has shown that combination treatment with a statin and t-PA after stroke increases cerebral blood flow and reduces infarct volume as compared with fibrinolytic treatment alone; 5 however, data in humans are lacking. Prompt reperfusion of the occluded artery is crucial to limiting the size of an infarct. The present study was designed to test the hypothesis that statin treatment before the onset of acute myocardial infarction (AMI) contributes to prompt coronary artery reperfusion and smaller infarct size in patients with AMI who receive fibrinolytic therapy. We examined the relationship between statin pretreatment and the rate of coronary artery reperfusion assessed according to the Thrombolysis In Myocardial Infarction (TIMI) 6 flow grade and infarct size in patients with AMI who were given fibrinolytic therapy. The degree of myocardial damage before and after reperfusion therapy was also assessed on the basis of electrocardiographic (ECG) findings. Methods Study PopulationWe enrolled 310 consecutive patients with ST-segment elevation AMI (mean age 60±11 years; 268 men, 42 women) who fulfilled the following criteria: (1) no history of myocardial infarction; (2) admission to Yokohama City University Medical Center within 12 h of symptom onset; (3) absence of conditions precluding the evaluation of ST-segment changes on ECG (left or right bundle-branch block, ventricular pacing); and (4) received fibrinolytic therapy. The diagnosis of AMI was based on typical chest pain lasting at least 30 min, ST-segment elevation of at least 1 mm in 2 contiguous leads, and a subsequent increase in the serum creatine kinase (CK) level to more than twice the upper limit of normal. Cardiac symptoms occurring within 48 h before the onset of AMI were defined as preinfarction angina. 7 In Yokohama City University Medical Center, in principle, patients without any contraindications for fibrinolysis were given 200 mg oral aspirin, 50 IU/kg intravenous heparin, and (Received June 11, 2008; revised

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Rosuvastatin Suppresses the Inflammatory Responses Through Inhibition of c-Jun N-terminal Kinase and Nuclear Factor-κB in Endothelial Cells

Abstract: This study suggests that the anti-inflammatory activity of rosuvastatin is accompanied by the inhibition of JNK and NF-kappaB.

Cited by 71 publications

References 27 publications

Expression of Prostaglandin E Synthases in Periodontitis

Expression of Prostaglandin E Synthases in Periodontitis

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

Effects of Pretreatment With Statins on Infarct Size in Patients With Acute Myocardial Infarction Who Receive Fibrinolytic Therapy

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