Effect Of Simvastatin Treatment Research Articles

Effect of Simvastatin Treatment on Mitochondrial Function and Inflammatory Status of Human White Adipose Tissue.

Statin therapy has shown pleiotropic effects affecting both mitochondrial function and inflammatory status. However, few studies have investigated the concurrent effects of statin exposure on mitochondrial function and inflammatory status in human subcutaneous white adipose tissue. In a cross-sectional study, we investigated the effects of simvastatin on mitochondrial function and inflammatory status in subcutaneous white adipose tissue of 55 human participants: 38 patients (19 females/19 males) in primary prevention with simvastatin (> 40 mg/d, > 3 mo) and 17 controls (9 females/8 males) with elevated plasma cholesterol. The 2 groups were matched on age, body mass index, and maximal oxygen consumption. Anthropometrics and fasting biochemical characteristics were measured. Mitochondrial respiratory capacity was assessed in white adipose tissue by high-resolution respirometry. Subcutaneous white adipose tissue expression of the inflammatory markers IL-6, chemokine (C-C motif) ligand 2 (CCL2), CCL-5, tumor necrosis factor-α, IL-10, and IL-4 was analyzed by quantitative PCR. Simvastatin-treated patients showed lower plasma cholesterol (P < .0001), low-density lipoprotein (P < .0001), and triglyceride levels (P = .0116) than controls. Simvastatin-treated patients had a lower oxidative phosphorylation capacity of mitochondrial complex II (P = .0001 when normalized to wet weight, P < .0001 when normalized to citrate synthase activity [intrinsic]), and a lower intrinsic mitochondrial electron transport system capacity (P = .0004). Simvastatin-treated patients showed higher IL-6 expression than controls (P = .0202). Simvastatin treatment was linked to mitochondrial respiratory capacity in human subcutaneous white adipose tissue, but no clear link was found between statin exposure, respiratory changes, and inflammatory status of adipose tissue.

The effect of simvastatin treatment on TNF-alpha-induced inflammation in human vascular endothelial cells (HUVECs)

The effect of simvastatin treatment on TNF-alpha-induced inflammation in human vascular endothelial cells (HUVECs)

Metabolite Signature of Simvastatin Treatment Involves Multiple Metabolic Pathways.

Statins inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme and are the most widely used medication for hypercholesterolemia. Previous studies on the metabolite signature of simvastatin treatment have included only a small number of metabolites. We performed a high-throughput liquid chromatography–tandem mass spectroscopy profiling on the effects of simvastatin treatment on 1098 metabolite concentrations in the participants of the METSIM (Metabolic Syndrome In Men) study including 1332 participants with simvastatin treatment and 6200 participants without statin treatment. We found that simvastatin exerts profound pleiotropic effects on different metabolite pathways, affecting not only lipids, but also amino acids, peptides, nucleotides, carbohydrates, co-factors, vitamins, and xenobiotics. We identified 321 metabolites significantly associated with simvastatin treatment, and 313 of these metabolites were novel. Our study is the first comprehensive evaluation of the metabolic signature of simvastatin treatment in a large population-based study.

Abstract 2332: Repurposing simvastatin to inhibit the mevalonate pathway as a therapeutic strategy to treat high-grade serous ovarian cancer

Abstract Introduction: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, and its five-year survival rate has not changed appreciably in decades. As such, there is an imperative need for new and innovative therapies. Our lab has previously discovered that metastatic ascites-derived tumor cells have acquired a gain-of-function p53 mutation following interaction with the ovarian microenvironment in our orthotopic murine model of EOC. This p53 mutation is associated with an upregulation of the mevalonate pathway, which is known for its vital role in producing cholesterol. Tumor cells upregulate metabolic pathways as a survival advantage to fuel their rapid growth and metastasis. Simvastatin, a statin therapy, specifically targets HMG-CoA reductase, the rate-limiting enzyme of this pathway, and inhibits its activity. As such, simvastatin may serve as a potential therapeutic opportunity for EOC. Gain-of-function p53 mutations in the epithelial cells of the distal fallopian tube is now widely accepted as the origin of high-grade serous ovarian cancer. Thus, the purpose of our study was to investigate the relationship between p53 status and the mevalonate pathway in oviductal epithelial (OVE) cells as well as evaluate the effect of simvastatin treatment on OVE cell viability. Methods/Results: OVE cells were isolated from the distal oviducts of FVB/N mice with a p53 wildtype status, and we either deleted the Trp53 gene or introduced a gain-of-function R175H p53 mutation using CRISPR/Cas9. Cell viability was measured following treatment with varying doses of simvastatin and p53 mutant cells showed the greatest sensitivity (IC50: 5.48 uM) compared to p53 wildtype (IC50: 14.80 uM) and p53 knockout (IC50:9.78 uM) cells. For subsequent experiments, OVE cells were treated with 10 uM simvastatin or DMSO and subjected to Resazurin, Transwell migration, CyQUANT proliferative and Caspase-Glo 3/7 assays. Simvastatin significantly decreased resazurin reduction to resorufin in a time-dependent manner over 48 hours, regardless of p53 status, demonstrating reduced metabolic activity. Additionally, OVE cell invasion was significantly reduced in simvastatin treated p53 mutant cells, compared to p53 wildtype or p53 knockout cells. Simvastatin treatment diminished cell proliferation and enhanced apoptotic activity in all simvastatin treated OVE cells. Conclusion: Overall, simvastatin appears to inhibit tumorigenic processes in vitro. The next steps of this project are to test simvastatin’s effect on disease regression in a novel murine oviductal cell injection model of EOC recently developed by our lab. In light of these results, repurposing simvastatin as a therapy for ovarian cancer may significantly improve the way we treat this vicious disease. Citation Format: Madison Pereira, Kathy Matuszewska, Jacob Haagsma, Alice Glogova, Trevor G. Shepherd, Jim Petrik. Repurposing simvastatin to inhibit the mevalonate pathway as a therapeutic strategy to treat high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2332.

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.

Effects of simvastatin on serum adiponectin: a meta-analysis of randomized controlled trials

BackgroundEffects of simvastatin on serum level of adiponectin, a protein conferring benefits in both cardiovascular and metabolic system, are not fully determined.MethodsA meta-analysis of randomized controlled trials (RCTs) was performed. Studies were identified by searching of Pubmed, Embase, and the Cochrane Library databases. Heterogeneity among the RCTs was determined by Cochrane’s Q test and I2 statistics. Meta-analysis was performed with random-effect model or fixed-effect model according to the heterogeneity. Meta-regression and subgroup analyses were performed to analyze the source of heterogeneity.ResultsTwelve RCTs with 16 comparisons and 1042 patients were included. Overall, serum adiponectin was not significantly affected by simvastatin (WMD: 0.42 μg/mL; 95% CI, -0.66–1.50 μg/mL). However, significant heterogeneity was detected (Cochrane’s Q test: p < 0.01; I2 = 83%). Subsequent meta-regression analyses indicated that treatment duration was a significant determinant of the effects of simvastatin treatment on serum adiponectin (Coefficient 0.04, p = 0.03). Subgroup analyses demonstrated that simvastatin treatment was associated with increased adiponectin in studies with treatment duration of 12 weeks (WMD: 3.65 μg/mL; p < 0.01), but not in studies with treatment duration of ≤ 8 weeks (WMD: -0.20 μg/mL; p = 0.38). The different between the two stratums was significant (p < 0.01).ConclusionsTreatment with simvastatin of 12 weeks may increase the serum level adiponectin in patients at risk for cardiovascular diseases, but not for the short term treatment of ≤ 8 weeks.

Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection.

Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.

Paraoxonase-1 and Simvastatin Treatment in Patients with Stable Coronary Artery Disease.

Background. Paraoxonase-1 (PON1) is the crucial antioxidant marker of high-density lipoproteins. The present study is aimed at assessing the effect of simvastatin treatment on PON1 activity and its relationship to Q192R and M55L polymorphisms in subjects with stable coronary artery disease (CAD). Methods. The patient group was composed of 53 individuals with stable CAD, and the control group included 53 sex-matched police officers without CAD. CAD patients were treated with simvastatin 40mg/day for 12 months. Respectively, flow mediated dilatation (FMD), serum hs-CRP and TNF-α levels, urinary 8-iso-PGF2α concentrations, and PON1 activity were evaluated in definitive intervals. Results. There was no effect of simvastatin treatment on urinary 8-iso-PGF2α. Simvastatin treatment significantly increased FMD value, decreased CRP and TNF-α concentration. After adjusting for PON1 genotypes, significantly higher PON1 activity was noted in the 192R allele carriers, in both groups. Regardless of genotype, PON1 activity remained stable after simvastatin treatment. Conclusions. The present study confirms a positive effect of simvastatin therapy on endothelial function and inflammatory markers in secondary prevention. Simvastatin treatment shows no effects on PON1 activity and 8-isoprostanes level. The effect of simvastatin therapy on PON1 activity is not modulated by Q192R and M55L polymorphisms.

Simvastatin Impairs Insulin Secretion by Multiple Mechanisms in MIN6 Cells.

Statins are widely used in the treatment of hypercholesterolemia and are efficient in the prevention of cardiovascular disease. Molecular mechanisms explaining statin-induced impairment in insulin secretion remain largely unknown. In the current study, we show that simvastatin decreased glucose-stimulated insulin secretion in mouse pancreatic MIN6 β-cells by 59% and 79% (p<0.01) at glucose concentration of 5.5 mmol/l and 16.7 mmol/l, respectively, compared to control, whereas pravastatin did not impair insulin secretion. Simvastatin induced decrease in insulin secretion occurred through multiple targets. In addition to its established effects on ATP-sensitive potassium channels (p = 0.004) and voltage-gated calcium channels (p = 0.004), simvastatin suppressed insulin secretion stimulated by muscarinic M3 or GPR40 receptor agonists (Tak875 by 33%, p = 0.002; GW9508 by 77%, p = 0.01) at glucose level of 5.5 mmol/l, and inhibited calcium release from the endoplasmic reticulum. Impaired insulin secretion caused by simvastatin treatment were efficiently restored by GPR119 or GLP-1 receptor stimulation and by direct activation of cAMP-dependent signaling pathways with forskolin. The effects of simvastatin treatment on insulin secretion were not affected by the presence of hyperglycemia. Our observation of the opposite effects of simvastatin and pravastatin on glucose-stimulated insulin secretion is in agreement with previous reports showing that simvastatin, but not pravastatin, was associated with increased risk of incident diabetes.

The effect of simvastatin treatment on endothelial cell response to shear stress and tumor necrosis factor alpha stimulation.

BackgroundStatin drugs are one of the most commonly prescribed pharmaceuticals by physicians. By blocking the rate-limiting step in the cholesterol biosynthesis pathway, statins inhibit cholesterol synthesis, which benefits patient health. However, since many other important cellular processes are regulated within this pathway, they may also be influenced by statin therapy. These pleiotropic effects of statins have not been fully investigated, but are believed to positively influence endothelial cells (ECs), which line the vasculature in a confluent monolayer. Few studies have considered the effect of blood flow on ECs and how this may augment EC response to statins.MethodsIn this study, the effect of statin treatment on ECs is investigated for cells stimulated with tumor necrosis factor alpha (TNF-α), an inflammatory cytokine that promotes an atheroprone endothelium. Additionally, ECs are exposed to a physiologically relevant wall shear stress (WSS) of 12.5 dynes/cm2 using a three-dimensional tissue culture model to provide a realistic hemodynamic environment. ECs are analyzed for morphology using light microscopy as well as cytoskeletal structure and alignment using confocal microscopy. Statistical analysis is performed on the results using both the one-way analysis of variance with Bonferroni post-tests and the two-tailed t test.ResultsWe have shown that statin treatment caused cells to adapt to a rounded, atheroprone morphology, with a significantly higher shape index. Oppositely, TNF-α stimulation caused cells to elongate to an atheroprotective morphology, with a significantly lower shape index. WSS and TNF-α were unable to reverse any statin-induced cell rounding or F-actin disruption.ConclusionFurther work is therefore needed to determine why statin drugs cause cells to have an atheroprone morphology, but an atheroprotective genotype, and why TNF-α stimulation causes an atheroprotective morphology, but an atheroprone genotype. Despite the morphological changes due to statins or stimulation, ECs still respond to WSS. Understanding how statins influence ECs will allow for more targeted treatments for hypercholestemia and potentially other diseases.

Protective effects of simvastatin on injured dopaminergic neurons in Parkinson's disease rats induced by lipopolysaccharide

Objective To examine the effect of simvastatin treatment on Parkinson's disease rats induced by lipopolysaccharide(LPS) and its mechanism. Methods The LPS-PD model was established by injection of LPS (5 mg/mL) into the right substantia nigra compacta (SNC), and rats were randomly divided into control group, LPS-model group and simvastatin treatment group with 15 rats in each group. Rats in the simvastatin treatment group was intraperitoneally administered simvastatin (5 mg/kg) before, and daily for 14 days after surgery, while the control group and LPS-model group received same volume normal saline and LPS respectively. Ionized calcium binding adaptor molecule 1 (Iba-1)-positive cells and the expression of tyrosine hydroxylase (TH), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the SNC were detected by immunohistochemistry, Western blotting and enzyme-linked immunosorbent assay, respectively. The effect of simvastatin in the PD model was also examined in behavioral tests. Results The LPS-model group exhibited typical animal PD behaviors. Compared with the control group, the LPS-model group exhibited a decreased number of DA neurons, and comparison of the intact side to reduce 81.13% (P<0.01) in the SNC, as well as increases in the Iba-1-positive cell number, iNOS, IL-1β and TNF-α expression (P<0.05). These effects were inhibited by simvastatin treatment (P<0.05). Conclusion Simvastatin mediates a protective effect on dopaminergic neurons in the SNC in the LPS-PD model, possibly by inhibiting glial cells (astrocytes and microglia) activation, and playing an anti-inflammatory role, thus improving substantia nigra function. Key words: Parkinson's disease; Simvastatin; Lipopolysaccharide; Glial cells

The effect of simvastatin treatment on bone repair of femoral fracture in animal model

The aim of this research was to evaluate the fracture healing area in osteoporotic femur of female rats restrained by stainless steel wire by statin administration in two different doses (5 mg and 20 mg). Ninety female rats were divided into six groups (n = 15): SH, SH-5 mg, SH-20 mg, OVX, OVX-5 mg, and OVX-20 mg. The surgery consisted of the fracture of the left femur bone and stabilization by K-wire and the administration was restricted and weekly controlled in the drinking water. The euthanasia was conducted at three different moments, five animals per period: 7 d, 14 d, and 28 d. Densitometry, zymography, and histological analyses showed a significant difference between some groups. According to these findings, simvastatin promoted a positive action for bone repair, especially in the osteometabolic group treated with 20 mg of the drug.

Comparative Study between Effect of Simvastatin (5 mg/Kg) and Simvastatin (50 mg/Kg) in an Early Treatment of Experimentally Induced Colitis in Mice

Inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) is a chronic intestinal inflammatory disease characterized by tissue edema, increased gut epithelial permeability, and extensive infiltration of the gut by leukocytes. Statins, in addition to their cholesterol-lowering activity, have pleiotropic effects, including immune-modulatory and anti-inflammatory effects. Simvastatin is a commonly prescribed statins with antioxidant and anti-inflammatory properties Thus; the aim of this study is to compare effect of simvastatin (5 mg/kg) and simvastatin (50 mg/kg) as an early treatment of experimentally induced ulcerative colitis in mice. For the first time in the current study, Simvastatin was administered after the appearance of signs and symptoms of the disease as an early treatment model. Twenty four mice were divided into four groups; control group, non treated DSS-induced colitis group, simvastatin (5 mg/kg/d) -treated DSS-induced colitis group, simvastatin (50 mg/kg/d) -treated DSS-induced colitis group. simvastatin at dose of (5 Original Research Article Elkatary et al.; BJMMR, 8(11): 937-947, 2015; Article no.BJMMR.2015.524 938 mg/kg/d) reduced MDA and TNF-α .While simvastatin at dose of (50 mg/kg/d) showed a significant increase in colon length of mice,a significant decrease in NO and MDA levels and a significant increase in r GSH level. Simvastatin (5 mg/kg/d) and (50 mg/kg/d) reduced the percentage of DAI by 25% and 41% respectively. The sums of histopathological scores were improved after simvastatin treatment. It can be concluded that effects of simvastatin treatment was mostly dose dependant. Unfortunately the high dose has no clinical application in human due to toxicity. So it is advised to use simvastatin with a dose of 5mg/kg as an early treatment of dss induced colitis model.

Modulatory role of simvastatin against aluminium chloride-induced behavioural and biochemical changes in rats.

Objectives. Aluminium, a neurotoxic agent in humans, has been implicated in the pathogenesis of neurodegenerative disorders. In this study, we examined the behavioral and biochemical effects of aluminium in rats with special emphasis on memory centres, namely, hippocampus and frontal cortex. Further, the effect of simvastatin treatment on aluminium intoxication was evaluated. Methods. Rats were exposed to aluminium chloride (AlCl3) for 60 days. Simvastatin (10 mg/kg/p.o.) and rivastigmine (1 mg/kg/p.o.) were administered daily prior to AlCl3. Behavioral parameters were assessed using Morris water maze test and actophotometer followed by biochemical investigations, namely, acetylcholinesterase (AChE) activity, TNF-α level, antioxidant enzymes (GSH, catalase), lipid peroxidation, and nitrite level in hippocampus and frontal cortex. Triglycerides, total cholesterol, LDL, and HDL levels in serum were also determined. Key Findings. Simvastatin treatment improved cognitive function and locomotor activity in rats. Simvastatin reversed hyperlipidemia and significantly rectified the deleterious effect of AlCl3 on AChE activity. Further, in hippocampus and frontal cortex, aluminium-induced elevation in nitrite and TNF-α and reduction in antioxidant enzymes were inhibited by simvastatin. Conclusion. To conclude, the present study suggests that simvastatin per se protects the neurons in hippocampus and frontal cortex from AlCl3, an environmental toxin.

Effect of Simvastatin on Arterial Stiffness in Patients with Statin Myalgia.

Statins reduce arterial stiffness but are also associated with mild muscle complaints. It is unclear whether individuals with muscle symptoms experience the same vascular benefit or whether statins affect striated and smooth muscle cells differently. We examined the effect of simvastatin treatment on arterial stiffness in patients who did versus those who did not exhibit muscle symptoms. Patients with a history of statin-related muscle complaints (n = 115) completed an 8 wk randomized, double-blind, cross-over trial of daily simvastatin 20 mg and placebo. Serum lipids and pulse wave velocity (PWV) were assessed before and after each treatment. Muscle symptoms with daily simvastatin treatment were reported by 38 patients (33%). Compared to baseline, central PWV decreased (P = 0.01) following simvastatin treatment but not placebo (drug ∗ time interaction: P = 0.047). Changes in central PWV with simvastatin treatment were not influenced by myalgia status or time on simvastatin (P ≥ 0.15). Change in central PWV after simvastatin treatment was inversely correlated with age (r = −0.207, P = 0.030), suggesting that advancing age is associated with enhanced statin-mediated arterial destiffening. In patients with a history of statin-related muscle complaints, the development of myalgia with short-term simvastatin treatment did not attenuate the improvement in arterial stiffness.

The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury

ObjectiveTo study the effect of simvastatin on neurological functional recovery after traumatic brain injuries (TBI) and the possible molecular mechanisms, we evaluated simvastatin-induced proliferation and differentiation of neural stem cells (NSCs) in vitro and in vivo and possible involvement of Notch-1 signaling in this process. MethodsAdult Wistar rats were randomly divided into three groups (n=28 for each): sham group, saline-treated group and simvastatin-treated group. Simvastatin was given orally at a dose of 1mg/kg/day starting at day 1 after TBI. At 1, 3, 7, 14, 21, 28, and 35 days after simvastatin treatment, functional outcome was measured using modified neurological severity scores (mNSS). Immunofluorescence of nestin was used to identify neurogenesis of NSCs in injured area of TBI rats. Western blot was applied to detect the expression level of Notch-1 protein in TBI rats with simvastatin. ResultsImmunostaining showed a significant increase in the number of nestin-positive cells in injured area of the simvastatin-treated group compared to that of the saline-treated group (p<0.05). In in vitro experiment, simvastatin induced enhanced proliferation and neurogenesis of cultured NSCs and elevated Notch-1 protein expression. Co-incubation of γ-secretase inhibitor, an inhibitor of Notch-1 pathway, with simvastatin abolished its neurorestoration effect. Most importantly, the simvastatin-treated group had significantly decreased mNSS at day 35 after TBI compared with the saline-treated group (p<0.05). ConclusionSimvastatin treatment enhanced neurological functional recovery after TBI possibly via activation of Notch signaling and increasing neurogenesis in the injured area.

Effect of simvastatin treatment on plasma visfatin levels in obese women

Aims: Obesity is one of the major concerns in the world currently, its prejudicial effect is exerted by proteins secreted by adipose tissue, among them visfatin was demonstrated to be related with BMI and cardiovascular diseases. The HMG-CoA reductase inhibitors are known to minimize the cardiovascular risk in hyperlipidemic patients and recently the discovery of various pleiotropic effects has made the statins evidencing among others anti-inflammatory effect. Our objective in this study was to determinate if simvastatin treatment may modulate visfatin levels in obese women without any other metabolic disorder.Methods: We recruited 25 obese women without any other metabolic disorder and treated with simvastatin for 6 weeks 20 mg/day.Results: The levels of plasma visfatin were similar before and after treatment (22 ± 20 versus 27 ± 14 ng/mL, p > 0.05) and correlated with BMI before treatment (p = 0.001). We also found correlations among visfatin and insulin levels (p = 0.015) and HOMA-IR (p = 0.025) only after treatment.Conclusion: These findings suggest that visfatin is not modulated by simvastatin treatment in this group but the treatment may interfere on the relation among visfatin, BMI, insulin and HOMA-IR.

The Effect of Simvastatin Treatment on Plasma Steroid Levels in Females with Non-classic Congenital Adrenal Hyperplasia

Non-classic congenital adrenal hyperplasia (NC-CAH) is one of the most frequent genetic disorders and its presence often results in androgen excess. 4 females with coexisting symptomatic NC-CAH and isolated hypercholesterolemia and 11 sex- and weight-matched control subjects with elevated cholesterol but normal steroid levels, participating in our study, were treated with simvastatin (20 mg daily). Throughout the whole period of simvastatin treatment, plasma levels of 17-hydroxyprogesterone, testosterone, androstendione and dehydroepiandrosterone sulfate in patients with NC-CAH remained lower compared with baseline, but increased in 2 patients after withdrawal of this drug. No changes in plasma steroids were observed in simvastatin-treated control subjects. Our findings suggest that simvastatin treatment may bring some benefits to symptomatic female patients with NC-CAH.

Abstract 1520: Simvastatin alters oxysterol profiles in TRAMP mice.

Abstract Due to mounting epidemiological data evidence, we sought to determine if simvastatin, the most widely used cholesterol lowering medication, could alter prostate cancer incidence in the TRAMP mouse model of prostate cancer. We hypothesized that simvastatin would inhibit advanced prostate cancer formation. Two separate studies were performed using high doses of simvastatin (up to 0.050% w/w) or simvastatin plus genistein in a high fat Western diet. While prostate cancer incidence was only moderately reduced, surprising changes in the serum oxysterol profiles of the TRAMP mice were detected. Oxysterols, oxygenated derivatives of cholesterol, have recently been shown to influence human diseases, and here we suggest that five oxysterols may play a role in prostate cancer progression. Ten mice were chosen from each treatment group, and their serum oxysterol profiles were analyzed by LC-MS-MS. The oxysterol that was most responsive to treatment was 24(S)-hydroxycholesterol, reducing significantly in all treatment groups. 24(S)-OHC was reduced from the control at 20 ng/mL to 10 ng/mL with statin treatment (p-value &amp;lt;0.001). 27-hydroxycholesterol was also reduced in the 0.044% simvastatin w/w dose to 10 ng/mL from 16 ng/mL in the control diet (p-value = 0.025). 5,6-dihydroxycholesterol responded to the 0.044% simvastatin diet lowering to 10 ng/mL as compared to the control of 18 ng/mL (p-value = 0.0002). 4-beta-hydroxycholesterol only responded to a combination of 0.050% simvastatin and 400 mg/kg genistein treatment, lowering from the control of 605 ng/mL down to 340 ng/mL with combination treatment (p-value &amp;lt;0.0001). Lastly 7-keto-cholesterol was reduced by the 0.044% simvastatin treatment, lowering to 44 ng/mL from the control of 67 ng/mL (p-value = 0.004). Future studies will determine how these oxysterols can influence signaling pathways that can affect prostate cancer progression. In summary, we have found an off target effect of simvastatin treatment in TRAMP mice. Although serum cholesterol parameters remain statistically similar, with no observable changes in LDL, HDL, triglycerides, or total cholesterol, serum oxysterol profiles were changed significantly with simvastatin treatment. Potentially one of the pharmacological mechanisms for the beneficial effects of statin treatment on cancer outcomes is not due to their cholesterol lowering abilities, but instead may hinge on their capacity to change the concentration of oxysterols in vivo. Citation Format: Sara K. Drenkhahn, Glenn A. Jackson, Nicholas J.E. Starkey, Yufei Li, Roxanne E. Gelven, Charles E. Wiedmeyer, Jim D. Browning, Kevin L. Fritsche, Cynthia L. Besch-Williford, Dennis B. Lubahn. Simvastatin alters oxysterol profiles in TRAMP mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1520. doi:10.1158/1538-7445.AM2013-1520

The effect of simvastatin treatment on behavioral parameters, cognitive performance, and hippocampal morphology in rats fed a standard or a high-fat diet

The aim of this study was to examine the effect of simvastatin (SMV), a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, in rats fed with a standard or a high-fat diet (HFD) throughout the prenatal and the postnatal periods. The emotional status of the animals was evaluated by elevated plus-maze and modified forced swimming tests, whereas cognitive performance was assessed by a Morris water maze task. Morphological changes in the hippocampus were examined by design-based stereology. HFD exposure significantly increased blood serum triglycerides without altering cholesterol levels relative to the controls. After four weeks of oral SMV (5 mg/kg) administration, serum triglycerides reverted to the control level. SMV caused significant anxiolytic, antidepressant-like, and nootropic effects in animals fed the standard diet. In the HFD group, enhanced anxiety and depression, and reduced cognitive performances of animals were reversed by SMV treatment. Although a total volume estimation of the hippocampal subfields indicated no significant change among the groups, the total number of pyramidal neurons decreased significantly in animals fed the HFD; following SMV treatment, this detrimental effect was reversed. In conclusion, chronic SMV administration has significant therapeutic potential for the treatment of affective and cognitive disorders with or without altering the serum lipid profiles.