2.Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice.
Xue-mei OU ; Yu-lin FENG ; Fu-qiang WEN ; Xiang-yang HUANG ; Jun XIAO ; Ke WANG ; Tao WANG
Chinese Medical Journal 2008;121(18):1821-1829
BACKGROUNDBleomycin-induced fibrosis is extensively used to model aspects of the pathogenesis of interstitial pulmonary fibrosis. This study aimed to determine the benefic effects and mechanisms of simvastatin on bleomycin-induced pulmonary fibrosis in mice.
METHODSBleomycin-induced pulmonary fibrosis mice were administered with simvastatin in different doses for 28 days. We measured inflammatory response, fibrogenic cytokines and profibrogenic markers in both bleomycin-stimulated and control lungs, and correlated these parameters with pulmonary fibrosis.
RESULTSSimvastatin attenuated the histopathological change of bleomycin-induced pulmonary fibrosis and prevented the increase of lung hydroxyproline content and collagen (I and III) mRNA expression induced by bleomycin. Moreover, simvastatin down-regulated the increased expression of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) induced by bleomycin at both gene and protein levels. Simultaneously, the accumulation of neutrophils and lymphocytes and the increased production of tumor necrosis factor-alpha (TNF-alpha) in bronchial alveolar lavage fluid were inhibited by simvastatin in early inflammatory phase after bleomycin infusion. The higher dose of simvastatin was associated with a more significant reduction in these inflammatory and fibrotic parameters. Furthermore, the inactivation of p38, RhoA and Smad2/3 signaling pathways was observed during simvastatin administration.
CONCLUSIONSSimvastatin attenuated bleomycin-induced pulmonary fibrosis, as indicated by decreases in Ashcroft score and lung collagen accumulation. The inhibitory effect of simvastatin on the progression of pulmonary fibrosis may be demonstrated by reducing inflammatory response and production of TGF-beta1 and CTGF. These findings indicate that simvastatin may be used in the treatment of pulmonary fibrosis.
Animals ; Antibiotics, Antineoplastic ; Bleomycin ; Mice ; Mice, Inbred C57BL ; Pulmonary Fibrosis ; chemically induced ; metabolism ; pathology ; Simvastatin ; pharmacology
3.Protective effect of simvastatin on kidney of rats with diabetes mellitus and the possible mechanism.
Xin WAN ; Xi WANG ; Fan-Lu LI ; Ya-Li WU ; Xin LIU ; Huan-Zhen CHEN ; Jing YANG ; Xiang-Li CUI
Chinese Journal of Applied Physiology 2018;34(4):313-317
OBJECTIVE:
To observe the protective effect of simvastatin on renal injury in diabetic rats and to explore the possible molecular mechanism.
METHODS:
Twenty-four SD rats were randomly divided into normal control (NC) group (=8) and modeling group (=16).The rats in modeling group were injected with streptozotocin intraperitoneally at a dose of 55 mg/kg to establishing diabetic rat model. After diabetic ratmodel established successfully, the diabetic rats were randomly subdivided into diabetes mellitus (DM) group and diabetes mellitus + simvastatin (DM+Sim) group (=8).Rats in DM+Sim group were given simvastatin at a dose of 40 mg/kg by oral gavages, once a day for 4 weeks. Morphological changes and interstitial fibrosis of kidney were observed by histopathological method. The expressions of relative protein in endoplasmic reticulum stress, inflammatory molecules in renal tissues and cells apoptosis were detected by molecular biology method.
RESULTS:
① Compared with NC group, the pathological changes of glomerulus and tubulointerstitium were obvious, and the collagen fibers were obviously erythrophilous and unevenly distributed in DM group. Compared with DM group, the morphological changes and fibrosis were significantly improved in DM+Sim group. ② The expressions of GRP78, p-IRE1α, NF-κB p65 and MCP-1 in DM group were significantly higher than those in NC group (<0.05), while the expressions of GRP78, p-IRE1α, NF-κB p65 and MCP-1in DM + Sim group were decreased (<0.05). ③ There were a small number of apoptotic nuclei in the glomeruli and adjunctive renal tubules in NC group detected by TUNEL assay, while there were a large number of apoptotic nuclei in DM group (<0.01). The number of apoptotic nuclei was decreased significantly in DM+Sim group (<0.01).
CONCLUSIONS
Morphologicalchanges and fibrosis of renal tissue are improved obviously, and the number of apoptotic cells is decreased significantly after administration of simvastatin in diabetic rats. Simvastatin exertsthe protective effect on diabetic nephropathy by inhibiting endoplasmic reticulum stress and NF-κB inflammatory signaling pathway, and reducing renal cell apoptosis.
Animals
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Diabetes Mellitus, Experimental
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Diabetic Nephropathies
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Kidney
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Rats
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Rats, Sprague-Dawley
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Simvastatin
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pharmacology
4.Expression of connective tissue growth factor and its down-regulation by simvastatin administration in pulmonary hypertensive rats.
Bin LIU ; Xian-min WANG ; Tong-fu ZHOU ; Yi-min HUA ; Han-min LIU ; Li WEI ; Li-na QIAO ; Xiao-qin WANG ; Shan-shan ZHAO ; Kun SHI
Chinese Journal of Pediatrics 2008;46(5):359-365
OBJECTIVETo explore the role of expression of connective tissue growth factor (CTGF) in pulmonary vascular remodeling of pulmonary hypertensive rats, and investigate the regulation of CTGF expression by simvastatin in this animal model.
METHODSEighty male Sprague-Dawley rats (350 to 400 g) were randomized to 7 groups. The rats in group PM(1 - 21) (n = 10) and PM(1 - 35) (n = 12) were treated with pneumonectomy + monocrotaline (MCT), and sacrificed at the 21st or 35th experimental day;those in groups PMS(1 - 35) (n = 12), PMS(21 - 35) (n = 12), PMV(1 - 35) (n = 12) and PMV(21 - 35) (n = 12) were given daily lavage of simvastatin (or vehicle) as intervention measure which began from the 1st and 21st experimental days, respectively; additional 10 rats were used as control without any intervention. The animals were sacrificed at the end of experiment (35 th day) as hemodynamic measurements and study on the morphological parameters relevant to pulmonary vascular remodeling were performed on each group of rats. The expression of ET-1 mRNA, CTGF mRNA and protein, and synthesis of collagen in these pneumonectomized, MCT-treated rats were compared between control and rats treated with simvastatin.
RESULTSRats in PM(1 - 35) Group developed severe PAH (mPAP = 39.75 +/- 3.62 mm Hg) (1 mm Hg = 0.133 kPa), right ventricular hypertrophy [RV/(LV + S) ratio = 0.627 +/- 0.040], and arterial medial hypertrophy (WT% = 61.73 +/- 5.39), these parameters of the control animals were 17.10 +/- 1.20 mm Hg, 0.262 +/- 0.018 and 14.71 +/- 1.16, respectively. CTGF mRNA and protein were mainly located in pulmonary arterial smooth muscle cells and interstitial macrophage shown by in situ hybridization and immunohistochemistry, respectively. The expression of ET-1 mRNA and CTGF mRNA detected by fluorescent quantitative RT-PCR in Group PM(1 - 35) were significantly increased in comparison with controls, and so did the CTGF protein expression determined by Western blotting in these diseased rats. The content of hydroxyproline (1.30 +/- 0.19 microg/mg wet lung) was remarkably higher than that of control animals (0.56 +/- 0.10 microg/mg wet lung). The up-regulation of ET-1 and CTGF gene expression, and elevated synthesis of hydroxyproline were reversed in rats intervened with simvastatin. The pulmonary hypertension, right ventricular hypertrophy and medial hypertrophy were attenuated in all simvastatin-treated rats no matter the intervention was initiated from the beginning or midway of the study.
CONCLUSIONThe up-regulation of CTGF gene expression may play an important role in the development of pulmonary vascular remodeling in PAH. Simvastatin can prevent and, to some extent, reverse the vascular remodeling via down-regulation of CTGF gene expression.
Animals ; Connective Tissue Growth Factor ; metabolism ; Down-Regulation ; Hypertension, Pulmonary ; metabolism ; physiopathology ; Male ; Rats ; Rats, Sprague-Dawley ; Simvastatin ; pharmacology
5.Effects of simvastatin on the immune-related genes of mouse osteoblasts.
Fei HU ; Xue-yang ZHANG ; Lei ZHOU
Chinese Journal of Stomatology 2009;44(4):222-226
OBJECTIVETo investigate the expression of immune-related genes during osteogenesis stimulated by simvastatin.
METHODSAfter treated with simvastatin, the expression of immune-related genes of mouse osteoblast was examined with gene chip (BiostarM-140s).
RESULTSThere were 16 differently expressed genes related to immune function, with nine down-regulated genes and seven up-regulated genes.
CONCLUSIONSAfter treated with simvastatin, expression of inflammation related genes is down-regulated and inflammation inhibitor genes is up-regulated in mouse osteoblasts.
Animals ; Down-Regulation ; Gene Expression Profiling ; Gene Expression Regulation ; Mice ; Osteoblasts ; drug effects ; immunology ; Osteogenesis ; drug effects ; Simvastatin ; pharmacology
6.Effect of simvastatin on bone morphogenetic protein-2 expression in the periodontal tissue after rat tooth movement.
Yuan-ping CHEN ; Guang-hong HAN ; Chang-wei JIN ; Rui-xin SHI ; Jian-hua HOU
Chinese Journal of Stomatology 2008;43(1):21-25
OBJECTIVETo investigate the effect of systematic administration of simvastatin on the bone morphogenetic protein-2 (BMP-2) expression in the periodontal tissue after rat tooth movement and on the relapse of tooth movement.
METHODSOrthodontic tooth movement of upper first molar was performed in 32 rats with coil spring for 21 days. The 32 rats were randomly allocated into 4 groups: negative control group (isotonic saline) and three experimental groups (2.5 mg x kg(-1), 5.0 mg x kg(-1) and 10.0 mg x kg(-1)). The simvastatin started to be administered to the experimental groups 1 day before appliances were removed, and once a day there after for 4 weeks. The negative control group received the isotonic saline only. The interdental distance between the first and second maxillary molars were measured, when appliances were removed, and 1 week and 4 weeks after that. After the rats were sacrificed, sections of first maxillary molar and periodontal tissue were studied by immunohistochemistry.
RESULTSThe number and percentage of relapse was lower in the three experimental groups than in the negative control group (P < 0.05, P < 0.01). The lower dose was given, the less relapse there was, with the lowerest dose resulting in lowest percentage of relapse (26.81% and 53.38%). BMP-2 expression in experimental groups was higher than in the negative control group, with the lowerest dose group showing the highest expression (P < 0.001). The BMP-2 expression on the tension side was slightly stronger than that on the compression side (P > 0.05).
CONCLUSIONSSystemic administration of simvastatin could decrease the extent of relapse of the orthodontic-moved tooth in rat, and the lower-dose of simvastatin seemed more effective. The possible mechanism for this may be that simvastatin functions by increasing the expression of BMP-2 in the periodontal tissue, accelerating the osteoblast activity and promoting bone formation.
Animals ; Bone Morphogenetic Protein 2 ; metabolism ; Male ; Periodontium ; drug effects ; metabolism ; Rats ; Rats, Wistar ; Simvastatin ; pharmacology ; Tooth Movement Techniques
8.Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-Induced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells.
Guo-Qiang ZHANG ; Yong-Kang TAO ; Yong-Ping BAI ; Sheng-Tao YAN ; Shui-Ping ZHAO
Chinese Medical Journal 2018;131(8):950-955
BackgroundOxidized low-density lipoprotein (ox-LDL)-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α-subunit (eIF2α)/CCAAT/enhancer-binding protein homologous protein (CHOP) endoplasmic reticulum (ER) stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells.
MethodsHuman umbilical vein endothelial cells (HUVECs) were treated with simvastatin (0.1, 0.5, or 2.5 μmol/L) or DEVD-CHO (selective inhibitor of caspase-3, 100 μmol/L) for 1 h before the addition of ox-LDL (100 μg/ml) and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance (ANOVA) followed by post hoc pairwise comparisons using Tukey's tests. A value of P < 0.05 was considered statistically significant.
ResultsExposure of HUVECs to ox-LDL resulted in a significant increase in apoptosis (31.9% vs. 4.9%, P < 0.05). Simvastatin (0.1, 0.5, and 2.5 μmol/L) led to a suppression of ox-LDL-induced apoptosis (28.0%, 24.7%, and 13.8%, F = 15.039, all P < 0.05, compared with control group). Ox-LDL significantly increased the expression of PERK (499.5%, P < 0.05) and phosphorylation of eIF2α (451.6%, P < 0.05), if both of which in the control groups were considered as 100%. Simvastatin treatment (0.1, 0.5, and 2.5 μmol/L) blunted ox-LDL-induced expression of PERK (407.8%, 339.1%, and 187.5%, F = 10.121, all P < 0.05, compared with control group) and phosphorylation of eIF2α (407.8%, 339.1%, 187.5%, F = 11.430, all P < 0.05, compared with control group). In contrast, DEVD-CHO treatment had no significant effect on ox-LDL-induced expression of PERK (486.4%) and phosphorylation of eIF2α (418.8%). Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment.
ConclusionsThis study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.
Apoptosis ; drug effects ; Cells, Cultured ; Endoplasmic Reticulum Stress ; drug effects ; Human Umbilical Vein Endothelial Cells ; drug effects ; metabolism ; Humans ; Lipoproteins, LDL ; pharmacology ; Oligopeptides ; pharmacology ; Simvastatin ; pharmacology
10.Protective effect of simvastatin on impaired intestine tight junction protein ZO-1 in a mouse model of Parkinson's disease.
Journal of Huazhong University of Science and Technology (Medical Sciences) 2015;35(6):880-884
Recently, several studies showed that gastrointestinal tract may be associated with pathophysiology of Parkinson's disease (PD). Intestine tight junction protein zonula occluden-1 (ZO-1) is an important component of intestinal barrier which can be degraded by matrix metallopeptidase 9 (MMP-9). In our previous study, a significant decline in ZO-1 was observed along with enhanced MMP-9 activity in the duodenum and distal colon of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In this study, the protective effect of simvastatin on ZO-1 was investigated using an MPTP mouse model of PD. Seven days after the end of MPTP application, the expression level of ZO-1 was evaluated by immunohistochemistry. The protein expression levels of ZO-1 and MMP9 were detected by Western blotting. Meanwhile, MMP-9 activity was analyzed by gelatin zymography. MPTP treatment led to a decrease in the expression of ZO-1, which was accompanied by elevated MMP-9 activity. Treatment with simvastatin could partly reverse the MPTP-induced changes in ZO-1 expression and reduce MMP-9 protein and activity. Taken together, these findings suggest that simvastatin administration may partially reverse the impairment of ZO-1 induced by MPTP via inhibiting the activity of MMP9, fortify the impaired intestinal barrier and limit gut-derived toxins that pass across the intestinal barrier.
Animals
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Disease Models, Animal
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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pharmacology
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Mice
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Parkinson Disease
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metabolism
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Simvastatin
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pharmacology
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Zonula Occludens-1 Protein
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drug effects