Mechanism Of Simvastatin Research Articles

Simvastatin induces pyroptosis via ROS/caspase-1/GSDMD pathway in colon cancer

BackgroundThe outcome of patients with colon cancer is still unsatisfied nowadays. Simvastatin is a type of statins with anti-cancer activity, but its effect on colon cancer cells remains unclear. The present study is intended to determine the underlying mechanism of simvastatin in treatment of colon cancer.MethodsThe viability and pyroptosis rate of cells treated and untreated with simvastatin were analysed by CCK-8 and flow cytometry assays, respectively. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production. Levels of pyroptosis markers were detected by western blotting analysis or immunofluorescence staining. Besides, the anticancer properties of simvastatin on colon cancer were further demonstrated using a cell line based xenograft tumor model.ResultsSimvastatin treatment in HCT116 and SW620 induced pyroptosis and suppressed cell proliferation, with changes in the expression level of NLPR3, ASC, cleaved-caspase-1, mature IL-1β, IL-18 and GSDMD-N. Moreover, inhibition of caspase-1 and ROS attenuated the effects of simvastatin on cancer cell viability. In addition, it was identified that simvastatin has an anti-tumor effect by down-regulating ROS production and inducing downstream caspase-1 dependent pyroptosis in the subcutaneous transplantation tumors of HCT116 cells in BALB/c nude mice.ConclusionsOur in vitro and in vivo results indicated that simvastatin induced pyroptosis through ROS/caspase-1/GSDMD pathway, thereby serving as a potential agent for colon cancer treatment.7bxpkuYS9tFbFRGefzbb2gVideo

Simvastatin promotes rat Achilles tendon-bone interface healing by promoting osteogenesis and chondrogenic differentiation of stem cells

To investigate the effect and mechanism of simvastatin on cell components of tendon-bone healing interface. The tendon-bone healing model was established by inserting the end of the Achilles tendon into the tibial tunnel on 24 rats, and simvastatin was used locally at the tendon-bone interface. Healing was evaluated at 8weeks by mechanical testing, micro-CT, and qualitative histology including H&E, Toluidine blue, and immunohistochemical staining. In vitro, bone marrow stromal cells (BMSCs) and tendon-derived mesenchymal stem cells (TDSCs) underwent osteogenic and chondrogenic differentiation respectively by plate co-culture. An analysis was performed on days 7 and 14 of cell differentiation. Biomechanical testing demonstrated a significant increase in maximum stiffness in the simvastatin-treated group. Micro-CT analysis showed that the bone tunnels in the simvastatin group were smaller in diameter and had higher bone density. H&E and Toluidine blue staining demonstrated that tendon-bone healing was significantly greater with better tissue arrangement and more extracellular matrix in the simvastatin-treated group than that in the control group, and immunohistochemical staining showed the expression of VEGF in simvastatin group was significantly higher. Histological staining and RT-PCR confirmed that simvastatin could promote the differentiation of co-cultured BMSCs and TDSCs into osteoblasts and chondroblasts, respectively. The effect of promoting osteogenic differentiation was more tremendous at 14days, while its effect on promoting chondroblast differentiation was more evident on the 7th day of differentiation. In conclusion, local administration of simvastatin can promote the tendon-bone healing by enhancing neovascularization, chondrogenesis, and osteogenesis in different stages of the tendon-bone healing process.

Fabrication of injectable bone substitute loading porous simvastatin-loaded poly(lactic-co-glycolic acid) microspheres

An injectable bone substitute (IBS) with well-controlled release mechanism of simvastatin (SIM) was fabricated from SIM loaded-porous poly(lactic-co-glycolic acid) microspheres (PLGA MSs), biphasic calcium phosphates (BCP) and CaCO3 nano powder as the solid phase and gelatin, citric acid and hydroxypropyl methylcellulose as the liquid phase. The ratios of PLGA MSs and BCP were varied to obtain IBS with optimal mechanical properties, biocompatibility and bioactivity. In vitro test with MG-63 pre-osteoblast cells showed that IBS with higher amount of PLGA MSs yield better cell adhesion and proliferation. In vivo study on rabbit femoral defect also suggested that the IBS promoted osteogenesis.

Prevention of post-operative complications by using a HMG-CoA reductase inhibitor in patients undergoing one-lung ventilation for non-cardiac surgery: study protocol for a randomised controlled trial

BackgroundPostoperative pulmonary complications (PPC) and peri-operative myocardial infarction (MI) have a significant impact on the long-term mortality of surgical patients. Patients undergoing one-lung ventilation (OLV) for surgery are at a high risk of developing these complications. These complications could be associated with intensive care unit (ICU) admissions and longer hospital stay with associated resource and economic burden. Simvastatin, a HMG-CoA reductase enzyme inhibitor has been shown to have pleiotropic anti-inflammatory effects as well as being endothelial protective. The benefits of statins have been shown in various observational studies and in small proof-of-concept studies. There is an urgent need for a well-designed, large clinical trial powered to detect clinical outcomes. The Prevention HARP 2 trial will test the hypothesis ‘simvastatin 80 mg when compared to placebo will reduce cardiac and pulmonary complications in patients undergoing elective oesophagectomy, lobectomy or pneumonectomy’.Methods/designThe Prevention HARP 2 trial is a UK multi-centre, randomised, double-blind, placebo-controlled trial. Adult patients undergoing elective oesophagectomy, lobectomy or pneumonectomy will be eligible. Patients who are already on statins will be excluded from this trial. Patients will be randomised to receive simvastatin 80 mg or matched placebo for 4 days pre surgery and for up to 7 days post surgery. The primary outcome is a composite outcome of PPC and MI within 7 days post surgery. Various secondary outcome measures including clinical outcomes, safety outcomes and health economic outcomes will be collected. The study aims to recruit 452 patients in total across 12 UK sites.DiscussionThe results of the Prevention HARP 2 trial should add to our understanding of the benefits of peri-operative statins and influence clinical decision-making. Analysis of blood and urine samples from the patients will provide insight into the mechanism of simvastatin action.Trial registrationInternational Standard Randomised Controlled Trials registry, ID: ISRCTN48095567. Registered on 11 November 2016.

Protective Effect and Potential Mechanism of Simvastatin on Myocardial Injury Induced by Diabetes with Hypoglycemia.

Simvastatin has been reported to reduce cardiovascular related morbidity and mortality in clinical trials which was independent of its cholesterol-lowering effect. This study aims to investigate the protective effect of simvastatin on myocardial injury caused by diabetic hypoglycemia and the possible underlying mechanism. We used streptozotocin (STZ) at a dose of 55 mg/kg to induce diabetes mellitus (DM) and over-dose insulin to induce hypoglycemia to establish diabetic hypoglycemia rat models. The cardiac protective effect of simvastatin treatment (at a dose of 40 mg/kg·d) upon diabetic hypoglycemia models was assessed. Ex vivo cardiac function, cardiomyocyte inotropic property and calcium transient were evaluated. The expression levels of microRNA (miRNA) and NF-κB in heart tissues were investigated. Both systolic and diastolic functions in diabetic rats were weakened, and further worsened in diabetic hypoglycemia rats, partially restored after administration of simvastatin. The protective effect of simvastatin on cardiac function under diabetic hypoglycermia was associated with decreased intracellular calcium and increased calcium sensitivity. miRNA array showed a differential profile of miRNA expression existed in diabetic hypoglycemia rats compared with diabetic non-hypoglycemia group, and that simvastatin could reverse the altered miRNA expression in diabetic hypoglycemia group. Simvastatin has protective effect on myocardial injury caused by diabetes with hypoglycemia, which is associated with increased calcium sensitivity, decreased NF-κB expression and altered miRNA expression profile.

Simvastatin and MBCD Inhibit Breast Cancer-Induced Osteoclast Activity by Targeting Osteoclastogenic Factors

ABSTRACTPrevious reports have documented that cholesterol-lowering simvastatin prevented osteolytic metastasis of breast cancer in animal model in which cancer cells were placed into blood circulation. Thus, simvastatin treatment might have a preventive effect in inhibiting osteoclast activity of metastatic bone microenvironment. This study documented that both simvastatin and MBCD (cholesterol depleting drug) blocked the breast cancer-induced TRAP and MMP activity, and expressions of various osteoclastogenic genes (TRAP, Cathepsin K, and NFATc1) in pre-osteoclast RAW264.7 cells, and osteoclastogenic CSF-1 and RANKL expressions in breast cancer MCF-7 cells. Thus, these findings unravel a molecular mechanism of simvastatin-/MBCD-mediated inhibition of breast cancer-driven osteoclast activity.

Preventive and therapeutic effect of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage.

To investigate the preventive and therapeutic effect and mechanism of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage. Sixty SD rat aged 9-12 weeks were chosen and divided into the control group, model group and simvastatin-treated group randomly with 20 rats in each group. Rats in the model group and simvastatin-treated group were infused with autologous fresh uncoagulated blood to the right brain tissue of the basal ganglia to build the cerebral hemorrhage model, while rats in the control group were treated with the same amount of normal saline. Then, rats in the simvastatin-treated group were given a gavage of 3mg/kg of simvastatin once a day after modeling. Rats in the three groups were given nerve dysfunction score (NDS) and wet-dry weighting method was used to detect the brain water content (BWC) of brain tissues around the lesion of the rats. Then Nissl staining was conducted and the undamaged neurons were counted. Immunohistochemical SP method was applied to count the number of NF-κB, TLR4 and IL-1β positive cells in brain tissues around the lesions, and the immuno fluorescence method was employed to determine the expression levels of NF-κB, TLR4 and IL-1β proteins. The NDS results of the simvastatin-treated group at all time points were all significantly higher than those of the model group (P<0.05); the BWC values of the simvastatin-treated group at all time points were all significantly lower than those of the model group at the same periods (P<0.05); the number of the undamaged neurons around the lesions of the simvastatin-treated group at all time points were all significantly higher than those of the model group (P<0.05); seven days after treatment, the number of the NF-κB, TLR4 and IL-1β positive cells in brain tissues around the lesions of the simvastatin-treated group were all significantly lower than those of the model group (P<0.05), and its expression levels of NF-κB, TLR4 and IL-1β protein were also significantly lower than those of the model group (P<0.05). Simvastatin can inhibit the expressions of NF-κB, TLR4 and IL-1β proteins in rats with cerebral hemorrhage, and protect neurons and reduce secondary inflammatory damages by down-regulating the above protein-mediated inflammatory responses.

Efficacy and Mechanism of Preoperative Simvastatin Therapy on Myocardial Protection after Extracorporeal Circulation.

Background Cardiopulmonary bypass (CPB) causes systemic inflammatory response and ischemia-reperfusion (IR) injury. Objective To investigate the effect and mechanism of simvastatin on myocardial injury in cardiac valve surgery with CPB. Methods One hundred thirty patients were randomly assigned to the statin group (n = 65) or control group (n = 65). Simvastatin was administered preoperatively and postoperatively. Duration of intensive care unit stay, duration of assisted ventilation, and left ventricular ejection fraction were recorded. Plasma was analysed for troponin T (cTnT), isoenzyme of creatine kinase (CK-MB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). Ultrastructure of the myocardium and autophagosomes were observed. Beclin-1, LC3-II/I, P62, AMPK, and the phosphorylation of AMPK in cardiomyocytes were detected. Results Simvastatin significantly reduced the duration of assisted ventilation (P = 0.030) and ejection fraction was significantly higher in the statin group (P = 0.024). Simvastatin significantly reduced the levels of cTnT, CK-MB, TNF-α, IL-6, and IL-8 (P < 0.05), reduced the expression of LC3-II/LC3-I and Beclin 1, and increased the expression of phosphorylation of AMPK. Simvastatin reduced the generation of autophagosomes and the ultrastructural injuries to myocardium. Conclusion Perioperative statin therapy reduced myocardial injury by regulating myocardial autophagy and activating the phosphorylation of AMPK. The registration number of this study is ChiCTR-TRC-14005164.

Simvastatin induces differentiation of rabbit articular chondrocytes via the ERK-1/2 and p38 kinase pathways

Statins are competitive inhibitors of hydroxy-methyl-glutaryl Coenzyme A (HMG-CoA) reductase, a key enzyme involved in the conversion of HMG-CoA to the cholesterol precursor mevalonate. Some statins, such as simvastatin (simvastatin), have been shown to have anti-cancer and anti-inflammatory effects, reducing cartilage degradation in osteoarthritic rabbits in vivo. However, the regulatory mechanisms undergirding simvastatin mediated chondrocyte differentiation have not been well elucidated. Thus, we investigated the action and mechanism of simvastatin on differentiation of rabbit articular chondrocytes through western blot analyses, RT-PCR, and immunohistochemical (IHC) and immunofluorescence (IF) staining. Simvastatin treatment was found to induce type II collagen expression and sulfated-proteoglycan synthesis in a dose- and time-dependent manner. Indeed, RT-PCR revealed increased expression of type II collagen on treatment with simvastatin. Both IHC and IF staining indicated differentiation of chondrocytes. Simvastatin treatment reduced activation of ERK-1/2 and stimulated activation of p38 kinase. Inhibition of ERK-1/2 with PD98059 enhanced simvastatin induced differentiation, whereas inhibition of p38 kinase with SB203580 inhibited simvastatin induced differentiation. Simvastatin treatment also inhibits loss of type II collagen in serial monolayer culture. Collectively, our results indicate that ERK-1/2 and p38 kinase regulate simvastatin-induced differentiation of chondrocytes in opposing manners. Thus, these findings suggest that simvastatin may be a potential therapeutic drug for osteoarthritis.

Effect of simvastatin on retinal Bcl-2/Bax expression and cell apoptosis in rats with ischemia-reperfusion injury

To explore the protective mechanism of simvastatin on retina ischemia-reperfusion injury in a rat model. It was a experiment study.One hundred and sixty-five adult male SD rats were randomly divided into three groups using digital table method, normal control group (CON, 55 rats), ischemia-reperfusion model group (MOD, 55 rats) and the medicine of simvastatin group (SIM, 55 rats).Each group was divided into five points in time of 4 hours, 8 hours, 16 hours, 24 hours and 48 hours, and there were 11 rats in each point. The right cephalic artery of each rat was clipped in model group and simvastatin group, but it was exposed in control group. Expression of Bcl-2 and Bax protein were determined by the immunohistochemical method, the number of cell apoptosis in retina were examined by the TUNEL method and express of Bcl-2 and Bax mRNA were measured by the real-time PCR method. The expression of proteins and mRNAs of Bcl-2 and Bax and also apoptosis of the rat retinas in each group at corresponding time point are compared using single factor analysis of variance and LSD-t test. Expression of Bcl-2 protein in model group began to decline at 4 h, reached the lowest at 24 h, with the data of (0.192 ± 0.011), (0.192 ± 0.015) , (0.189 ± 0.015), (0.183 ± 0.012) and (0.187 ± 0.010) .Expression of Bcl-2 protein in simvastatin group were higher than model group at each time point, with the information of (0.208 ± 0.011), (0.220 ± 0.011) , (0.221 ± 0.014), (0.228 ± 0.007) and (0.206 ± 0.015). The numbers were statistically significant at corresponding time point in each group (F(4, 8, 16, 24, 48) = 8.079, 9.005, 9.904, 35.563, 8.810, P < 0.05). Expression of Bax protein in model group began to increased at 4 h, reached the highest at 24 h, with the data of (0.255 ± 0.010), (0.261 ± 0.033), (0.276 ± 0.025), (0.324 ± 0.037) and (0.234 ± 0.018). Expression of Bax protein in simvastatin group were lower than model group at each time point, with the information of (0.222 ± 0.012), (0.219 ± 0.017), (0.223 ± 0.008), (0.232 ± 0.021) and (0.214 ± 0.008). The numbers were statistically significant at corresponding time point in each group (F(4, 8, 16, 24, 48) = 16.601, 13.525, 10.303, 25.849, 13.805, P < 0.05). AI of retina in model group began to increased at 4 h, reached the highest at 24 h, with the data of (11.771 ± 0.722), (13.705 ± 0.512), (15.533 ± 0.370), (21.210 ± 1.221) and (17.660 ± 0.414). AI of retina in simvastatin group were lower than model group at each time point, with the information of (9.061 ± 0.289), (11.717 ± 0.565), (13.506 ± 0.541), (16.586 ± 0.488) and (14.428 ± 0.559). The numbers were statistically significant at corresponding time point in each group (F(4, 8, 16, 24, 48) = 87.096, 232.245, 575.564, 389.205, 771.658, P < 0.05). Bcl-2 mRNA in model group were lower than in control group at each time point, with the data of (0.360 ± 0.017), (0.232 ± 0.066), (0.314 ± 0.012), (0.179 ± 0.019) and (0.357 ± 0.084). But Bcl-2 mRNA in simvastatin group were higher than those in model group, with the information of (1.718 ± 0.247), (1.981 ± 0.317), (1.309 ± 0.031), (1.289 ± 0.209) and (0.684 ± 0.071). The differences had statistical significance at corresponding time point in each group (F(4, 8, 16, 24, 48) = 112.934, 109.750, 3534.800, 112.428, 128.140, P < 0.05). And Bax mRNA in the model group were higher than those in control group at each time point, with the data of (2.140 ± 0.288), (3.189 ± 0.492), (2.896 ± 0.466), (2.392 ± 0.119) and (1.789 ± 0.169). However, Bax mRNA in simvastatin group were lower than those in model group, with the information of (0.658 ± 0.197), (1.746 ± 0.315), (0.670 ± 0.221), (0.952 ± 0.164) and (0.575 ± 0.174). The differences had statistical significance at corresponding time point in each group (F(4, 8, 16, 24, 48) = 74.115, 54.504, 81.271, 243.743, 97.163, P < 0.05). Simvastatin has protective effects on retinal ischemia reperfusion injury, and the mechanism is closely related to inhibiting retinal cell apoptosis by adjusting the express of Bcl-2 and Bax.

Effects of varying doses of simvastatin on protein kinase A in immature rabbits with chronic heart failure

Objective To investigate the effects of varying doses of simvastatin (SIM) on protein kinase A(PKA), ventricular remodeling and heart function in immature rabbits with chronic heart failure (CHF), to explore the possible mechanisms for simvastatin on CHF. Methods Sixty male immature rabbits were randomly divided into 5 groups: control (CON) group, CHF model group, small-dose simvastatin (SD-SIM) group[SIM concentration was 0.3 mg/(kg·d)], medium-dose simvastatin (MD-SIM)group[SIM concentration was 1.5 mg/(kg·d)], and the high-dose simvastatin (HD-SIM)group[SIM concentration was 3.0 mg/(kg·d)]. The general condition of immature rabbits in the experiment group was evaluated.Color doppler ultrasonography was used to detect the left ventricular structure and the function.The left ventricular myocardium was taken and fixed in paraformaldehyde (40 g/L). The expression of PKA was evaluated by immunohistochemical assay. Results In CON group, the rabbits were all alive; in the other groups, most immature rabbits were unhairing, with diet reduction, weight lose and sluggish with hyperkeratosis.Overall survival rate was 82%(49/60 cases). The mortality rate in CHF model group was significantly higher than that in the MD-SIM group(41.7% vs 8.3%, P<0.05). Compared with the CON group, left ventricular ejection fraction(LVEF) in the SD-SIM group, HD-SIM group and CHF model group all dropped sharply (all P<0.01), while the left ventricular end diastolic diameter (LVEDd) and left ventricular end systolic diameter (LVESd) increased markedly (all P<0.01). Compared with CHF model group, LVEDd and LVESd decreased and LVEF increased significantly in SD-SIM group, HD-SIM group and MD-SIM group(all P<0.05), the effects of MD-SIM group was the best(P<0.05). LVEF in MD-SIM group increased significantly compared with SD-SIM group, HD-SIM group and CHF model group (all P<0.05). PKA expression in SD-SIM group, MD-SIM group and HD-SIM group increased significantly compared to the CHF model group and CON group (all P<0.01). Compared with the SD-SIM group and HD-SIM group, the expression of MD-SIM group significantly increased (P<0.05). Conclusions Simvastatin can reverse the left ventricular remodeling and improve the heart function of immature rabbits with CHF.The effect of MD-SIM was the best.The mechanism of simvastatin may be correlated to up-regulating the expression of PKA. Key words: Simvastatin; Adriamycin; Chronic heart failure; Protein kinase A

Effects of different doses of simvastatin on connective tissue growth factor and osteoprotegerin of immature rabbits with chronic heart failure

Objective To observe the effects of different doses of simvastatin on immature rabbit models of chronic heart failure(CHF) and to explore the mechanism of simvastatin in the rabbits with CHF. Methods Sixty male immature rabbits were randomly divided into 5 groups: control(CON) group, CHF group, small-dose simvastatin(SD-SIM) group, medium-dose simvastatin(MD-SIM) group, and the high-dose simvastatin(HD-SIM) group, 12 cases in each group.The models of CHF were established by injecting adriamycin(ADR) via the auricular vein of rabbits.In the first injection of ADR, simvastatin tablets [concentration of 0.3, 1.5, 3.0 mg/(kg·d), respectively] were given to the rabbits by intragastric administration for SD-SIM, MD-SIM, and HD-SIM models.The general conditions of immature rabbits in experiment group were evaluated.Hemodynamic data were detected.HE staining was used to observe structure of myocardial cells.The plasma level of osteoprotegerin(OPG) was measured by enzyme-linked immunosorbent assay (ELISA). The expression of connective tissue growth factor(CTGF) was evaluated by immunohistochemical assay. Results 1.In CON group, the rabbits were all alive; in CHF, SD-SIM, MD-SIM and HD-SIM groups, most immature rabbits had skinchapped, unhaired and sluggish with hyperkeratosis, diet reduction, and losing weight.Overall survival rate was 76.7%.2.Hemodynamic data indicated that the + dp/dtmax, -dp/dtmax and the left ventricular systolic pressure (LVSP) in the SD-SIM, HD-SIM and CHF groups dropped significantly compared with the CON group (all P<0.05). There was a remarkable increase in the SD-SIM, HD-SIM and MD-SIM groups compared with CHF group (all P<0.01); and there was a remarkable drop in the cardiac function of the SD-SIM and HD-SIM groups compared with MD-SIM group (P<0.05).3.Compared with the CON group, CTGF and OPG expression in the SD-SIM, MD-SIM, HD-SIM and CHF groups increased significantly (P<0.01), while the expression in the SD-SIM, MD-SIM and HD-SIM groups decreased significantly compared with that of the CHF group (P< 0.05). Compared with the MD-SIM group, the expression of CTGF and OPG in the SD-SIM and HD-SIM groups increased significantly (P<0.05). Conclusions Simvastatin can improve cardiac function of rabbits with CHF significantly, and the effect on MD-SIM group is the best.The mechanism of simvastatin may depress the expressions of CTGF and OPG.CTGF and OPG can predict CHF. Key words: Simvastatin; Chronic heart failure; Connective tissue growth factor; Osteoprotegerin

Simvastatin Inhibits Proliferation and Induces Apoptosis in Human Lung Cancer Cells

Lung cancer is the one of the most frequent causes of malignant tumors. In recent years, it has been documented that statins have anticancer and cancer chemopreventive properties. However, the mechanism of simvastatin on lung cancer is still unclear. In this study, the human lung cancer cell line A549 cells were incubated with simvastatin. Simvastatin inhibited the survival of A549 cells in a dose-dependent manner, decreased Bcl-2 protein expression, and increased Bax protein expression time and dose dependently. In addition, simvastatin blocked cells in the G1 phase of the cell cycle, downregulated cyclin D1 and CDKs protein expression, mediated the mitochondria-dependent caspase cascade by increasing caspase-3, -8, and -9 mRNA and protein expression, downregulated Xiap levels to induce cells apoptosis. Importantly, simvastatin suppressed decreased MMP-9 protein expression and suppressed NF-κB activation in A549 cells. Taken together, these results showed that the anticancer effect of simvastatin in lung cancer A549 cells via the inhibiting cell proliferation, influencing the cell cycle, downregulating cyclin D1 and CDKs expression, inducing apoptosis, and decreasing MMP-9 levels, possibly by inhibiting the activation of NF-κB. Statins contribute to lung cancer therapy and may be an ideal anticancer and cancer chemopreventive agent for lung cancer.

HMG-CoA Reductase Inhibitor Regulates Endothelial Progenitor Function Through the Phosphatidylinositol 3′-Kinase/AKT Signal Transduction Pathway

HMG-CoA reductase inhibitor (statins) are known to have pleiotropic effects. We examined the effect and mechanism of simvastatin on peripheral endothelial progenitor cells (EPCs). Rats were divided into simvastatin group and the control group after cardiac infarction operation. Simvastatin treatment significantly increased the number of peripheral blood CD34+ CD133+ cells, and serum concentration of vascular endothelial growth factor (VEGF) and AKT was markedly increased in vivo. In cultured EPC, simvastatin increased the concentrations of VEGF, AKT and eNOS. Western blots analysis showed that simvastatin increased the phosphorylation of eNOS and FKHRL1, which can be blocked by the PI3K/AKT pathway blocker LY294002 . Our study demonstrated that simvastatin increases the mobilization of EPCs after cardiac infarction. In in vitro study, simvastatin increases the phosphorylation of eNOS and of FKHRL1 through the PI3K/AKT signaling pathway.

Anti-inflammatory Mechanism of Simvastatin in OVA-specific Mouse Allergic Asthma

Anti-inflammatory Mechanism of Simvastatin in OVA-specific Mouse Allergic Asthma

Mechanism of simvastatin on induction of heat shock protein in osteoblasts

It has recently been reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) stimulate bone formation. However, the mechanism of stimulation of bone metabolism by statins is not precisely clarified. In this study, we investigated whether simvastatin induces heat shock protein (HSP) 27, HSP70, and HSP90 in osteoblast-like MC3T3-E1 cells. Simvastatin increased the levels of HSP27 while having little effect on the levels of HSP70 or HSP90. The effect of simvastatin on HSP27 accumulation was dose dependent. Cycloheximide reduced the accumulation. Simvastatin induced an increase in the levels of mRNA for HSP27. Actinomycin D suppressed the mRNA levels. Simvastatin induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase among the MAP kinase superfamily. SB203580 and PD169316, inhibitors of p38 MAP kinase, suppressed the HSP27 accumulation by simvastatin while SB202474, a negative control of p38 MAP kinase inhibitor, had no effect. SB203580 reduced the simvastatin-increased mRNA levels for HSP27. Lovastatin, another statin, also induced the HSP27 accumulation and SB203580 suppressed the HSP27 accumulation. These results strongly suggest that statins such as simvastatin do not stimulate the induction of HSP70 and HSP90, but do stimulate the induction of HSP27 in osteoblasts and that p38 MAP kinase plays a role in this induction.