OBJECTIVE: In addition to lowering cholesterol, statins exert pleiotropic effects on endothelial cells. Bone morphogenetic proteins (BMPs) have recently been implicated in vascular inflammation and disease. We set out to investigate the effect of statins on BMP endothelial cell precursor-derived regulator (BMPER), a novel member of the BMP pathway. METHODS AND RESULTS: Mevastatin enhanced BMPER expression in cultured endothelial cells in a time- and concentration-dependent manner as determined by immunocytochemistry, RT-PCR, and Western blotting. Similar effects were observed in vitro and in vivo using simvastatin. Actinomycin D chase analysis and BMPER promoter reporter assays revealed that this is mostly a posttranscriptional event resulting in prolonged BMPER RNA half-life. We confirmed that the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase/actin pathway is involved using the specific pathway activator cytotoxic necrotizing factor of Yersinia pseudotuberculosis, which prevented upregulation of BMPER expression by mevastatin and pathway inhibitors (C3-toxin, RhoAN19 mutant, fasudil, and cytochalasin D) that enhanced BMPER expression. Increasing concentrations of BMPER exert antiinflammatory features in endothelial cells as reflected by intercellular adhesion molecule-1 downregulation. Accordingly, silencing of BMPER enhances intercellular adhesion molecule-1 expression. Furthermore, mevastatin reduced the expression of proinflammatory BMP4, a well-known direct interaction partner of BMPER. CONCLUSIONS: Mevastatin modulates the BMP pathway by enhancing BMPER via the RhoA/Rho-associated coiled-coil containing protein kinase Rho kinase/actin pathway, as well as by reducing BMP4 expression. BMP4 downregulation and BMPER upregulation contribute to the antiinflammatory pleiotropic effects of statins. less...

Statins are cholesterol-lowing drugs with pleiotropic effects including cytotoxicity to cancer cells. In this study, we investigated the signaling pathways leading to apoptosis by simvastatin. Simvastatin induced cardinal features of apoptosis including increased DNA fragmentation, disruption of mitochondrial membrane potential (MMP), and increased caspase-3 activity by depleting isoprenoids in MethA fibrosarcoma cells. Interestingly, the simvastatin-induced apoptosis was accompanied by p53 stabilization involving Mdm2 degradation. The apoptosis was ameliorated in p53 knockdown clones of MethA cells as well as p53(-/-) HCT116 cells. The stabilized p53 protein translocated to mitochondria with Bax, and cytochrome c was released into cytosol. Moreover, knockdown or deficiency of p53 expression reduced both Bax translocation to mitochondria and MMP disruption in simvastatin-induced apoptosis. Taken together, these all indicate that stabilization and translocation of p53 to mitochondria is involved in Bax translocation to mitochondria in simvastatin-induced apoptosis. less...

PURPOSE: The case of a patient whose International Normalized Ratio (INR) increased with concurrent use of ophthalmic erythromycin and warfarin is reported. SUMMARY: A 77-year-old Caucasian woman began therapy with warfarin for thromboembolism prophylaxis secondary to atrial fibrillation (target INR, 2-3). Warfarin was prescribed by her cardiologist, and care was established with clinical pharmacists in an anticoagulation clinic. She was receiving a weekly maintenance dosage of 14 mg. She had a history of atrial fibrillation, hyperlipidemia, osteoarthritis, hypothyroidism, coronary artery disease, myocardial infarction, congestive heart failure, and breast cancer. In addition to warfarin, the patient had been receiving alprazolam, carvedilol, furosemide, levothyroxine sodium, lisinopril, nitroglycerin, potassium chloride, propoxyphene hydrochloride- acetaminophen, simvastatin, and trazodone. After receiving warfarin at the same weekly dosage for over four months, the patient's ophthalmologist prescribed erythromycin ophthalmic ointment for chronic bacterial conjunctivitis. Three weeks later, her INR was found to be 8.5. A total of four warfarin doses were withheld, and her weekly maintenance dosage of warfarin was subsequently decreased to 12 mg. Five weeks later, her INR was 1.5, and it was determined that the erythromycin ophthalmic ointment had been discontinued five days prior. Her weekly maintenance dosage of warfarin was increased to 16 mg. Rechallenge with erythromycin five days before her next INR measurement resulted in an INR of 4.2. A new weekly maintenance dosage of 13 mg was established, and her subsequent INRs were within normal range. CONCLUSION: An increase in INR values was reported after initiation of ophthalmic erythromycin in a patient receiving warfarin and recurred upon rechallenge with ophthalmic erythromycin. less...

BACKGROUND: Statins are thought to have tumorolytic properties, reducing angiogenesis by inhibiting pro-angiogenic factors and inducing apoptosis of mural pericytes within the tumor vascular tree. MATERIALS AND METHODS: An orthotopic mouse glioblastoma (GL-26) model was used to investigate the effect of simvastatin on glioblastoma vasculature in vivo. GL-26 cells were implanted into the striatum of C5LKa mice treated with either control, low- or high-dose simvastatin. Brains were analyzed for necrotic volume, apoptosis, morphology and pericytic cells within the vascular tree. RESULTS: Low-dose simvastatin increased necrosis and apoptosis compared to both control and high-dose simvastatin groups. High-dose simvastatin increased vessel caliber by reducing pericytic cells along the tumor vessel wall compared to both control and low-dose simvastatin groups. CONCLUSION: Simvastatin has a dual effect on tumorigenesis. At high doses, it may worsen instead of 'normalizing' tumor angio-architecture, albeit low doses affect tumor cell survival by promoting necrosis and apoptosis. less...

Statins inhibit 3-hydroxy-3-methyl-glutarylcoenzyme CoA (HMG-CoA) reductase, the proximal enzyme for cholesterol biosynthesis. They exhibit pleiotropic effects and are linked to health benefits for diseases including cancer and lung disease. Understanding their mechanism of action could point to new therapies, thus we investigated the response of primary cultured human airway mesenchymal cells, which play an effector role in asthma and COPD, to simvastatin exposure. Simvastatin induced apoptosis involving caspase-9, -3 and -7, but not caspase-8 in airway smooth muscle cells and fibroblasts. HMG-CoA inhibition did not alter cellular cholesterol content but did abrogate de novo cholesterol synthesis. Pro-apoptotic effects were prevented by exogenous mevalonate, geranylgeranyl pyrophosphate and farensyl pyrophosphate, downstream products of HMG-CoA. Simvastatin increased expression of Bax, oligomerization of Bax and Bak, and expression of BH3-only p53-dependent genes, PUMA and NOXA. Inhibition of p53 and silencing of PUMA expression partly counteracted simvastatin induced cell death, suggesting a role for p53-independent mechanisms. Simvastatin did not induce mitochondrial release of cytochrome c, but did promote release of inhibitor of apoptosis (IAP) proteins, Smac and Omi. Simvastatin also inhibited mitochondrial fission with loss of mitochondrial Drp1, an essential component of mitochondrial fission machinery Thus, simvastatin activates novel apoptosis pathways in lung mesenchymal cells involving p53, IAP inhibitor release, and disruption of mitochondrial fission. less...

Introduction: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, named statins, are well-established cholesterol lowering drugs able to reduce cardiovascular risk in hypercholesterolemic patients. The possible effect of statin on bone tissue, so-called pleiotropic effects has received particular attention. Studies reported a positive effect of statin on bone tissue in both of animal and human study by enhancing the expression of the bone morphogenetic proteins (BMPs), in particular of BMP2, which in turn leads to osteoblast differentiation and bone formation including interfering with osteoclastic activity. In a systematic review, the lipophilic statin as simvastatin had positive effect to bone mineral density (BMD) better than the more hydrophilic statin such as atorvastatin and fluvastatin. This study was aimed to compare efficacy of medical therapy between HMG-CoA reductase inhibitor and Non-HMG-CoA reductase inhibitor group to changing of bone mineral density and bone markers in the patients with hyperlipidemia. Materials and methods: A prospective randomized control trial study was enrolled the 212 hyperlipidemia with osteopenia patients to study in year 2006-2008. All subjects were randomized to 2 groups between statin and non-statin group the patients were screened by inclusion criteria and measured in bone mineral density (BMD), bone marker and blood chemistry. All data were analyzed by difference of changing in bone marker and BMD between statin and non-statin groups using paired T-test. Results: The present study showed 212 hyperlipidemia with osteopenia patients which of 106 patients in statin group had mean age (63.17 + 9.51 years) and the same number of patients in non-statin group had mean age (60.96 + 8.9 years). All subjects were 63 patients in male and 149 patients in female. Difference of bone formation marker and BMD between after and before was significantly higher than in statin group and the difference of bone resorption marker was also significantly lower than in statin group Conclusion: The lipophilic statin as moderate to high dose of simvastatin had beneficial positive effect to increasing BMD and could be additive use for prevention of bone loss in hyperlipidemia patients. less...

PURPOSE: To investigate whether simvastatin use is associated with visual field (VF) stabilization in patients with normal tension glaucoma (NTG). DESIGN: Prospective cohort study (ClinicalTrials.gov Identifier: NCT00321386). PARTICIPANTS: A total of 256 eyes from 256 Chinese subjects with NTG. METHODS: Patients were followed up at 4-month intervals for 36 months for VF progression per Anderson's criteria. Clinical parameters were checked for association with progression in multivariate analysis. MAIN OUTCOME MEASURES: The primary outcome was the association between simvastatin use and VF progression. RESULTS: Thirty-one patients (12.1%) were taking simvastatin (statin+), and 225 patients (87.9%) were not taking simvastatin (statin-). Baseline age, gender, untreated intraocular pressure, VF indices, vertical cup-to-disc ratio, and central corneal thickness (CCT) were comparable between the 2 groups. There were significantly more patients with a history of hypercholesterolemia, systemic hypertension, and ischemic heart disease in the statin+ group. A total of 121 patients (47.3%) showed evidence of VF progression (mean rate of mean deviation loss was -0.30 decibel per year) during the 36 months of follow-up. Simvastatin use was among 8 of 121 patients (6.6%) who progressed compared with 23 of 135 patients (17.0%) who did not progress (P = 0.011). Logistic regression revealed that history of disc hemorrhage (relative risk [RR] 3.26; 95% confidence interval [CI], 1.21-8.76; P = 0.019), history of cerebrovascular accidents (RR 2.28; 95% CI, 1.03-5.06; P = 0.043), and baseline age (per 10 years older; RR 1.38; 95% CI, 1.08-1.76; P = 0.009) were significant risk factors for VF progression, whereas simvastatin use conferred a protective effect (RR 0.36; 95% CI, 0.14-0.91; P = 0.030). CONCLUSIONS: Simvastatin use may be associated with VF stabilization in patients with NTG. A larger scale randomized controlled trial and cost-effectiveness analyses seem warranted. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article. less...

Since macrophages play an important role in the destabilization of atherosclerotic plaques, and smooth muscle cells (SMCs) contribute to plaque stability, selective clearance of macrophages in atherosclerotic plaques is a promising strategy for plaque stabilization. In the present study, we investigated the effects of fluvastatin, simvastatin, lovastatin and pravastatin on the viability of macrophages and SMCs. All statins, except pravastatin, induced cell death of J774A.1 macrophages after 24h, albeit with different sensitivity. The viability of rabbit aortic SMCs was hardly affected. Fluvastatin-induced macrophage cell death was characterized as apoptosis and could be reversed by isoprenoid intermediates of the mevalonate pathway. Peritoneal macrophages from male or female mice were much more resistant to statin-induced cell death. The high sensitivity of J774A.1 macrophages to statin-induced cell death was related to the strong HMG-CoA reductase activity in these cells. Macrophage and SMC content of rabbit atherosclerotic plaques was not affected after in vitro treatment with fluvastatin or lovastatin for 3 days. In conclusion, fluvastatin, simvastatin and lovastatin, but not pravastatin, can selectively induce apoptosis in J774A.1 macrophages, but not in SMCs, primary macrophages or rabbit atherosclerotic plaques. This effect was related to the degree of HMG-CoA reductase activity in the different cell types. less...

Drug delivery technology is a practically promising way to enhance the therapeutic efficacy of drugs. However, there remain some properties of material to be improved for drug delivery, such as the biodegradability and biocompatibility. In this study, we demonstrate that a biodegradable hydrogel of gelatin can achieve the sustained release of water-insoluble simvastatin. Biologically active simvastatin can be released accompanied with the biodegradation of hydrogel. The biocompatibility issue of material remaining after drug release can be practically resolved. Simvastatin was water-solubilized by gelatin grafted with L-lactic acid oligomer and mixed with gelatin, followed by chemical crosslinking to obtain gelatin hydrogels incorporating simvastatin water-solubilized. The hydrogel augments the simvastatin-induced bone regeneration given biocompatible gelatin fragments and has its potential to deliver a wide range of water-insoluble drugs. less...

Sustained activation of Akt kinase acts as a focal regulator to increase cell growth and survival, which cause tumorigenesis including breast cancer. Statins, potent inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, display anticancer activity. The molecular mechanisms by which statins block cancer cell growth are poorly understood. We demonstrate that in the tumors derived from MDA-MB-231 human breast cancer cell xenografts, simvastatin significantly inhibited phosphorylation of Akt with concomitant attenuation of expression of the anti-apoptotic protein Bcl(XL). In many cancer cells, Bcl(XL) is a target of NFkappaB. Simvastatin inhibited the DNA binding and transcriptional activities of NFkappaB resulting in marked reduction in transcription of Bcl(XL). Signals transmitted by anti-neoplastic mechanism implanted in the cancer cells serve to obstruct the initial outgrowth of tumors. One such mechanism represents the action of the tumor suppressor protein PTEN, which negatively regulates Akt kinase activity. We provide the first evidence for significantly increased levels of PTEN in the tumors of simvastatin-administered mice. Importantly, simvastatin markedly prevented binding of NFkappaB to the two canonical recognition elements, NFRE-1 and NFRE-2 present in the PTEN promoter. Contrary to the transcriptional suppression of Bcl(XL), simvastatin significantly increased the transcription of PTEN. Furthermore, expression of NFkappaB p65 subunit inhibited transcription of PTEN, resulting in reduced protein expression, which leads to enhanced phosphorylation of Akt. Taken together, our data present a novel bifaceted mechanism where simvastatin acts on a nodal transcription factor NFkappaB, which attenuates the expression of anti-apoptotic Bcl(XL) and simultaneously derepresses the expression of anti-proliferative/proapoptotic tumor suppressor PTEN to prevent breast cancer cell growth. less...