Therapeutic Effects Of Simvastatin Research Articles

Therapeutic effects of simvastatin on Galectin-3 and oxidative stress parameters in endotoxemic lung tissue.

Galectins constitute of a soluble mammalian β-galactoside binding lectin family, which play homeostatic roles in the regulation of the cell cycle, and apoptosis, in addition to their inflammatory conditions. Galectin-3 has an important role in the regulation of various inflammatory conditions including endotoxemia, and airway inflammation. Statins, the key precursor inhibitors of 3-hydroxyl-3-methyl coenzyme A (HMG-CoA) reductase, may prevent the progression of inflammation in sepsis after prior statin treatment. Endotoxemia leads to the formation of oxidative stress parameters in proteins, carbohydrates, and DNA. In the present study, we aimed to show the effects of simvastatin on Galectin-3, and glutathione reductase (GR), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and thiobarbituric acid reactive substances (TBARS) levels in lung tissue of rats which were treated with lipopolysaccharides (LPS) during the early phase of sepsis. Rats were divided into four groups as the control, LPS (20 mg/kg), simvastatin (20 mg/kg), and simvastatin+LPS group. Galectin-3 expression in formalin-fixed paraffin-embedded lung tissue sections was demonstrated by using the immunohistochemistry methods. There were reduced densities, and the decreased number of Galectin-3 immunoreactivities in the simvastatin+LPS group compared with the LPS group in the pneumocytes, and in the bronchial epithelium of lung tissue. In the LPS group, GR, GSH-Px, and SOD were found lower than the levels in simvastatin-treated LPS group (P<0.05, P<0.01, P<0.01 respectively) in the lung tissue. However, TBARS decreased in the simvastatin+LPS group compared with the levels in LPS group (P<0.001). Simvastatin attenuates LPS-induced oxidative acute lung inflammation, oxidative stress, and suppresses LPS-induced Galectin-3 expression in the lung tissue.

Inhibition of the RhoA/Rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension

ABSTRACTBackground: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. Methods: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i.p.) on the first day of the study. The MCT + simvastatin group received simvastatin (2 mg/kg) daily for 4 weeks, after which pulmonary arterial pressure was measured by right heart catheterization. The protein and mRNA levels of Rho and ROCK1 were measured by immunohistochemistry, Western blot, and PCR. For in vitro experiments, human pulmonary endothelial cells were divided into seven groups: control, simvastatin, monocrotaline pyrrole (MCTP), MCTP + simvastatin, MCTP + simvastatin + mevalonate, MCTP + simvastatin + farnesyl pyrophosphate (FPP), and MCTP + simvastatin + FPP + geranylgeranyl pyrophosphate (GGPP). After 72 h exposed to the drugs, the protein and mRNA levels of RhoA and ROCK1 were measured by Western blot and PCR. Results: The MCT group showed increased mean pulmonary arterial pressure, marked vascular remodeling, and increased protein and mRNA levels of RhoA and ROCK1 compared to the other groups (P < 0.05). In vitro, the MCTP group showed a marked proliferation of vascular endothelial cells, as well as increased protein and mRNA levels of RhoA and ROCK1 compared to the MCTP + simvastatin group. The MCTP + simvastatin + mevalonate group, MCTP + simvastatin+ FPP group, and MCTP + simvastatin + FPP + GGPP group showed increased mRNA levels of RhoA and ROCK1, as well as increased protein levels of RhoA, compared to the MCTP + simvastatin group. Conclusions: Simvastatin improved vascular remodeling and inhibited the development of PAH. The effects of simvastatin were mediated by inhibition of RhoA/ROCK1. Simvastatin decreased RhoA/ROCK1 overexpression by inhibition of mevalonate, FPP, and GGPP synthesis.

Simvastatin inhibits the apoptosis of hippocampal cells in a mouse model of Alzheimer's disease.

Alzheimer's disease is associated with cognitive impairments that affect memory and executive functions. Simvastatin is a cholesterol-lowering statin drug that is used to control levels of cholesterol in the blood, particularly in cases of hypercholesterolemia, and may be used in the treatment of aneurysmal subarachnoid hemorrhage. Previous results have indicated that the apoptosis of hippocampal cells may serve a critical role in the progression of Alzheimer's disease. In the present study, it was determined whether Simvastatin inhibited the apoptosis of hippocampal cells in vitro and in vivo. The therapeutic effects of Simvastatin were evaluated in 24-month-old triple-transgenic Alzheimer's disease (3×Tg-AD) mice, and the efficacy of Simvastatin in attenuating memory and cognitive impairment was investigated. Levels of apoptosis-related gene expression in the hippocampus and hippocampal cells of experimental mice were also detected. In addition, neuron excitability was assessed in the functionally relevant brain regions in the hippocampus. The data indicated that Simvastatin significantly suppressed the apoptosis of hippocampal cells in 3×Tg-AD model mice compared with controls (P<0.01). Furthermore, treatment with Simvastatin improved the dementia status of 3×Tg-AD mice, as determined by a learning task in which mice exhibited significantly reduced attention impairment, impulsivity and compulsivity (P<0.01). In addition, results demonstrated that Simvastatin significantly inhibited hippocampal damage and significantly improved neuronal loss in hippocampal structures classically associated with attentional performance when compared with untreated mice (P<0.01). Thus, Simvastatin prevented cognitive impairment by decreasing hippocampal cell apoptosis and improving learning-memory ability. Simvastatin treatment also increased the expression of anti-apoptotic genes and decreased the expression pro-apoptotic genes (P<0.01), which may have been associated with improved motor attention and cognitive competence in 3×Tg-AD mice. Collectively, these preclinical data indicated that Simvastatin was efficient in attenuating memory lapse and hippocampal cell apoptosis in a 3×Tg-AD mouse model. Thus, Simvastatin may be useful in improving the clinical outcome of patients with Alzheimer's disease.

Effects of simvastatin on airway inflammation and airway mucus hypersecretion in rats with chronic obstructive pulmonary disease

To explore the preventive and therapeutic effects of simvastatin on rats with chronic obstructive pulmonary disease (COPD) and examine the mechanism of airway inflammation and airway mucus hypersecretion. The rat model of COPD was established by cigarette smoking and an intratracheal injection of lipopolysaccharide (LPS). A total of 18 male Sprague-Dawley rats were randomly divided into control, COPD and simvastatin groups (n=6 each). The control and COPD groups received normal saline once daily via intragastric administration (i.g.) while the simvastatin group had simvastatin (0.5 g/L) 1 ml/100 g once daily via i.g. Pulmonary function was tested and pathological changes in bronchus and lung were observed. The bronchoalveolar lavage fluid (BALF) levels of interleukin-8 (IL-8), interleukin-17 (IL-17) and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expressions of intercellular adhesion molecule 1 (ICAM-1), nuclear factor κB (NF-κB), mucin 5AC (MUC5AC) and Toll-like receptor 4 (TLR4) in rat airway were detected by immunohistochemical staining. The mRNA and protein expressions of TLR4 and MUC5AC in bronchi and lung tissue were detected by fluorescent real time quantitative polymerase chain reaction (RT-PCR) and Western blot. The changes of bronchi and lung tissues in COPD group were consistent with typical pathological manifestations of COPD. As compared with the COPD group, the degree of pulmonary pathological damage and the decline of pulmonary function in the simvastatin group were significantly lessened, but still remarkable as compared with the control group. The BALF levels of IL-8, IL-17 and TNF-α in the smvastatin group [(484.4 ± 11.1), (78.9 ± 2.0), (192.7 ± 2.0) ng/L] were significantly lower than those in the COPD group [(605 ± 48.7), (89.9 ± 6.9), (212.6 ± 10.7) ng/L], but still higher than those in the control group [(341.2 ± 21.4), (56.0 ± 2.9), (127.5 ± 9.0) ng/L respectively] (all P <0.01). Compared with COPD group, the expression levels of ICAM-1, NF-κB, MUC5AC and TLR4 protein were significantly lower in the simvastatin group, but still higher than the control group (all P <0.01). Furthermore, the expression levels of mRNA and protein of MUC5AC and TLR4 were significantly lower in the simvastatin group than those in the COPD group (all P <0.05). In COPD model rats, simvastatin can decrease the levels of IL-8, IL-17 and TNF-α in BALF and inhibit the expression levels of ICAM-1, NF-κB, MUC5AC and TLR4 protein in airway and lung tissue. Thus it plays preventive and therapeutic roles by reducing airway inflammation and airway mucus hypersecretion.

Abstract A22: Combined simvastatin and anti-IGF-1R therapy of prostate cancer cells in co-culture with bone

Abstract Prostate cancer frequently metastasizes to the bone. Bone metastases show weak responses to the conventional therapies given today, and patients with metastases cannot be cured. Bone matrix is rich in stored growth factors, with IGF-1 being one of the most abundant. IGF-1 acts as a survival factor for tumor cells and we speculate that bone-derived IGF-1 weakens the effects of therapies aimed to target bone metastases and, furthermore, that effects of apoptosis inducing therapies could be enhanced if given in combination with therapies inhibiting the IGF-1 receptor (IGF-1R). Simvastatin inhibits the mevalonate pathway and have been found to induce apoptosis of prostate cancer cells. The aims of this study were to confirm stimulating effects of bone-derived IGF-1 on prostate cancer cell growth and to test if IGF-1R inhibition could enhance simvastatin therapy effects on prostate cancer cells in a bone environment. Prostate cancer PC-3 and 22Rv1 cells were co-cultured with mice calvarias for 72 h and showed significantly increased cell numbers compared to when cultured alone. A phospho-RTK array confirmed activation of the IGF-1R on PC-3 and 22Rv1 cells by calvaria-conditioned media, and neutralization of bone-derived IGF-1 abolished the calvaria-induced increase of PC-3 cell growth. Treatments of PC-3 and 22Rv1 cells with simvastatin and the IGF-1R inhibitor NVP-AEW541 reduced tumor cell numbers and cell viability, and induced apoptosis, as assessed by flow cytometry analysis of Annexin-V. Combined s imvastatin and NVP-AEW541 treatments resulted in enhanced growth inhibitory effects compared to either therapy given alone. Expression analysis by RT-PCR and Western blot indicated that the therapeutic effects of simvastatin involved down-regulation of the IGF-1R in PC-3 cells and of the constitutively active androgen receptor AR-V7 variant in 22Rv1 cells. In conclusion, we believe that a combination of IGF-1R inhibition with simvastatin, and possibly other apoptosis inducing therapies, can provide novel and improved treatment regimes for prostate cancer bone metastases. Citation Format: Annika Nordstrand, Marie Lundholm, Andreas Larsson, Ulf Lerner,Anders Widmark, Pernilla Wikström. Combined simvastatin and anti-IGF-1R therapy of prostate cancer cells in co-culture with bone [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A22.

Assessment of the efficacy of different statins in murine collagen‐induced arthritis

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used lipid-lowering agents. In addition to their well-known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen-induced arthritis, a well-described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model. Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols. Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti-type II collagen IgG production), and biochemical (interleukin-6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels. This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune-mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.

Anti-atherosclerotic effect of simvastatin depends on the presence of apolipoprotein E

Low density lipoprotein receptor deficient (LDLR-KO) and apolipoprotein E deficient (apo E-KO) mice both develop hyperlipidemia and atherosclerosis by different mechanisms. The aim of the present study was to compare the effects of simvastatin on cholesterol levels, endothelial dysfunction, and aortic lesions in these two models of experimental atherosclerosis. Male LDLR-KO mice fed a high cholesterol (HC; 1%) diet developed atherosclerosis at 8 months of age with hypercholesterolemia. The addition of simvastatin (300 mg/kg daily) to the HC diet for 2 more months lowered total cholesterol levels by ∼57% and reduced aortic plaque area by ∼15% compared with the LDLR-KO mice continued on HC diet alone, P<0.05. Simvastatin treatment also improved acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in isolated aortic rings, which was associated with an increase in NOS-3 expression by ∼88% in the aorta measured by real time polymerase chain reaction (PCR), P<0.05. In contrast, in age-matched male apo E-KO mice fed a normal diet, the same treatment of simvastatin elevated serum total cholesterol by ∼35%, increased aortic plaque area by ∼15%, and had no effect on endothelial function. These results suggest that the therapeutic effects of simvastatin may depend on the presence of a functional apolipoprotein E.