Endothelial dysfunction in streptozotocin-diabetic rats is not reversed by dietary probucol or simvastatin supplementation

Summary Oxidative stress and dyslipidaemia are key features of diabetes mellitus and may be involved in mediating the vascular endothelial dysfunction associated with this disease. The aim of this study was to examine the effect of dietary lipid-lowering and antioxidant agents on vascular endothelial function and oxidative stress. Diabetic male Sprague-Dawley rats (i. v. streptozotocin, 45 mg/kg) were fed for 4 weeks on a standard diet or on a diet supplemented with either the lipid-lowering antioxidant probucol (1 % w/w in diet) or the 3-hydroxy 3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor simvastatin (0.01 % w/w in diet). Responses to noradrenaline, acetylcholine, and sodium nitroprusside were assessed in small mesenteric arteries (mean internal diameter 300 ± 5 μm, n = 80) mounted on a small vessel myograph. Plasma concentrations of total cholesterol and triglycerides were significantly raised in standard-fed diabetic rats and significantly reduced in probucol and simvastatin-fed diabetic rats. 8-epi-prostaglandin (PG)F₂α, an indicator of oxidative stress, was raised in liver and aorta from diabetic rats compared to controls. Probucol supplementation reduced 8-epi-PGF₂α in aorta and liver of diabetic rats but increased 8-epi-PGF₂α content in plasma and aorta from control animals. The abnormal relaxation to acetylcholine in arteries from the diabetic rats (pEC₅₀ diabetic 6.763 ± 0.172 vs control 7.541 ± 0.175; p < 0.05) was not improved by probucol or simvastatin. These data, therefore, do not support a role for oxidative stress or dyslipidaemia in mediating the impaired ACh-induced endothelium-dependent relaxation of small mesenteric arteries from the streptozotocin-diabetic rat. [Diabetologia (1998) 41: 157–164] Received: 4 August 1997 and in revised form: 29 September 1997     

自噬对高胆固醇饮食大鼠下颌骨结构改变的影响研究

目的    探讨自噬对高胆固醇饮食大鼠下颌骨结构改变的影响及辛伐他汀的治疗效果。方法　将30只SD大鼠随机分为正常饮食组（NC组）10只、高胆固醇组20只;喂养24周后,高胆固醇组再随机分成两组,每组10只,一组继续喂养高胆固醇饲料（HC组）,另一组在高胆固醇饲料中加入5 mg/kg辛伐他汀（HC+SIM组）。喂养32周后,取大鼠空腹血进行生化检测;处死大鼠后对下颌骨进行骨组织形态分析;实时荧光定量PCR（qRT-PCR）及免疫组织化学染色检测各组自噬相关基因Lc3及p62的mRNA和蛋白表达水平。结果　（1）3组总胆固醇和低密度脂蛋白水平总的比较,差异均有统计学意义（F值分别为21.539、16.596,均P < 0.05）;其中NC组和HC+SIM组总胆固醇和低密度脂蛋白水平均低于HC组（均P < 0.05）,而NC组和HC+SIM组组间比较,差异无统计学意义（P > 0.05）。（2）与NC组比较,HC组大鼠骨体积分数、骨小梁厚度、骨小梁数目明显下降,而骨小梁间隔增加,Lc3及p62 mRNA表达水平明显升高,差异均有统计学意义（均P < 0.05）;与HC组比较,HC+SIM组骨体积分数、骨小梁厚度、骨小梁数目均明显升高,骨小梁间隔减小,p62 mRNA和蛋白表达水平明显下降,差异均有统计学意义（均P < 0.05）;而NC组和HC+SIM组这些指标组间比较,差异均无统计学意义（均P > 0.05）。结论    自噬可能参与调控高胆固醇饮食大鼠下颌骨结构的改变,辛伐他汀能够改善高胆固醇饮食导致的大鼠下颌骨微结构的破坏     

Statins and Contrast-induced Acute Kidney Injury with Coronary Angiography

BackgroundContrast-induced acute kidney injury is an adverse outcome resulting from radiocontrast medium exposure during coronary angiography and percutaneous coronary intervention.MethodsA systematic search was conducted to retrieve studies that investigated the impact of statin exposure before coronary angiography or percutaneous coronary intervention on the development of contrast-induced acute kidney injury. The primary outcome was the development of contrast-induced acute kidney injury. We separately analyzed statin/placebo comparisons and high-/low-dose statin comparisons.ResultsFifteen randomized controlled trials met inclusion criteria: 11 studies with statin-naïve subjects, 2 studies with chronic statin users, and 2 studies with unspecified prior statin exposure. Statin exposure reduced the risk of contrast-induced acute kidney injury relative to placebo (relative risk [RR] 0.63, P = .01) with a nonsignificant reduction in the need for hemodialysis (RR 0.25, P = .08). This benefit was also observed in high-dose versus low-dose statin trials (RR 0.46, P = .004), in statin-naïve patients (RR 0.53, P <.0001), and with all studied statins. Higher statin exposure reduced contrast-induced acute kidney injury in patients with acute coronary syndromes compared with placebo or low-dose statins (RR 0.49, P <.00001), with no significant benefit among patients undergoing elective procedures (RR 0.86, P = .50). Subgroup analyses confirmed the benefit of statins in patients with diabetes, chronic kidney disease, congestive heart failure, and those receiving >140 mL of contrast dye.ConclusionStatin therapy is effective at reducing the risk of contrast-induced acute kidney injury. It should thus be considered, at least on a short-term basis, for patients at increased risk of this complication.     

Efficacy of Subgingivally Delivered Simvastatin in the Treatment of Patients With Type 2 Diabetes and Chronic Periodontitis: A Randomized Double‐Masked Controlled Clinical Trial

Background: Simvastatin (SMV) is a specific competitive inhibitor of 3‐hydroxy‐2‐methyl‐glutaryl coenzyme A reductase. Recently, it has been reported that statins promote bone formation. The present study is designed to investigate the effectiveness of 1.2% SMV in an indigenously prepared, biodegradable, controlled‐release gel as an adjunct to scaling and root planing (SRP) in the treatment of patients with type 2 diabetes and chronic periodontitis (CP). Methods: Thirty‐eight patients were categorized into two treatment groups: SRP plus 1.2% SMV and SRP plus placebo. Clinical parameters were recorded at baseline before SRP and at 3, 6, and 9 months; they included modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). At baseline and after 6 and 9 months, radiologic assessment of intrabony defect (IBD) fill was done using computer‐aided software. Results: Mean PD reduction and mean CAL gain were found to be greater in the SMV group than the placebo group at 3, 6, and 9 months. Furthermore, significantly greater mean percentage of bone fill was found in the SMV group (32.64% ± 12.90%) compared to the placebo group (4.22% ± 9.75%) after 9 months. Conclusion: There was a greater decrease in mSBI and PD and more CAL gain with significant IBD fill at sites treated with SRP plus locally delivered SMV in patients with type 2 diabetes and CP.     

Improvement of Endothelial Dysfunction with Simvastatin in Patients with Autosomal Dominant Polycystic Kidney Disease

Cardiovascular problems are a major cause of morbidity and mortality in patients with autosomal dominant polycystic kidney disease (ADPKD). Endothelial dysfunction (ED), which is an early manifestation of vascular injury, has been shown in patients with ADPKD. Statins have a beneficial effect in the reversal of ED. The aim of this study was to investigate the effects of a statin, simvastatin, on ED in patients with ADPKD. Sixteen patients with ADPKD having well-preserved renal function were included in the study. Endothelial function of the brachial artery was evaluated by using high-resolution vascular ultrasound. Endothelial-dependent dilatation (EDD) was expressed as the percentage change in the brachial artery diameter from baseline to reactive hyperemia. After the baseline evaluations of EDDs, patients were started treatment with simvastatin at a dose of 40 mg/day and were treated for six months. EDDs were recalculated after one and six months of therapy. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein were also measured as markers of inflammation. Baseline EDD was 11.3 ± 6.9% in patients with ADPKD. After one month of simvastatin treatment, EDD increased significantly to 14.6 ± 4.6 % (P = 0.016 versus baseline). Endothelial-dependent dilatation further increased significantly to 18.9 ± 7.5 % (P = 0.011 versus baseline, P = 0.048 versus first month) after six months of therapy. There was also a significant decrease in the level of IL-6 from 21.6 ± 21.7 pg/mL to 9.1 ± 3.5 pg/mL (P= 0.002).

Six months of simvastatin therapy resulted in a significant improvement of ED in patients with ADPKD. This finding may be in part related to the pleiotropic effects of simvastatin.     

不同剂量辛伐他汀治疗慢性阻塞性肺疾病的疗效、安全性及对肺功能影响

目的 探讨不同剂量辛伐他汀治疗慢性阻塞性肺疾病（COPD）的疗效、安全性及对肺功能的影响。方法 选取2015年7月—2016年1月于榆林市第二医院接受治疗的COPD患者192例作为研究对象,采用随机数字表法分为A、B两组,各96例。A组患者使用辛伐他汀剂量为40 mg/d,B组患者使用剂量为20 mg/d。两组均进行为期6个月的治疗。比较两组患者临床疗效、肺功能[主要指标包括第一秒用力呼气容积（FEV1）、第一秒用力呼气容积占预计值百分比（FEV1%）、用力肺活量（FVC）]、生活质量及安全性。结果 A组治疗1个月时总有效率（82.29%）与B组（70.83%）相比差异不明显;治疗3个月（89.85% vs 77.08%）及6个月时（93.75% vs 84.38%）均明显高于B组,差异有统计学意义（P<0.05）。治疗1个月时两组肺功能各指标差异不明显,治疗3个月及6个月时A组各指标均明显优于B组,差异有统计学意义（P<0.05）。治疗后两组生活质量均得到明显好转,A组患者生活质量明显优于B组,差异有统计学意义（P<0.05）。两组患者用药安全性比较无显著差异。结论 大剂量辛伐他汀治疗COPD疗效及安全性良好,可显著改善肺功能并提高患者生活质量,值得临床推广应用。     

Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression

BACKGROUND: Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme-A reductase, the rate-limiting enzyme of the mevalonate pathway, and are used successfully in the treatment of hypercholesterolaemia. Statins are contraindicated during pregnancy. Lately, we have shown that simvastatin has adverse affects on human first trimester placental explants' proliferation and migration. The objective of the present study was to investigate the molecules involved in mediating simvastatin's effect on trophoblast cell migration. We hypothesized that simvastatin attenuates insuline-like growth factor-I (IGF-I) receptor expression (involved in trophoblast motility), matrix metalloproteinase (MMP) activities, and heat shock protein 27 (HSP27) levels (whose mRNA is actively transcribed during trophoblast differentiation) in trophoblast cells thus consequently effecting their migration. METHODS: Human placental explants were cultured above a matrigel with/without simvastatin (10 microM) for 5 days. In this model, trophoblast migrates from the villi into the matrigel. Western-blot and immunohistochemistry served for analysing HSP27 expression. Immunohistochemistry was used for assessing IGF-I receptor localization. MMPs activity was assayed by gel zymography. RESULTS: Simvastatin reduced IGF-I receptor membranal expression, MMP2 activity and HSP27 expression in trophoblast cells (P < 0.05). CONCLUSIONS: The inhibitory effect of simvastatin on trophoblast cell migration is associated with a significant decrease in the tested molecules, which probably contributes to the impaired migration.     

Subcutaneous administration of lactone form of simvastatin stimulates ectopic osteoinduction by rhBMP-2

OBJECTIVE: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. MATERIALS AND METHODS: Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. RESULTS: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group. CONCLUSION: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.     

Co-administration of ezetimibe and simvastatin in acute myocardial infarction

BACKGROUND: Recent trials in acute myocardial infarction indicate that intensive and early statin therapy that lowers low-density lipoprotein cholesterol (LDL-C) to < or = 70 mg dL(-1) is beneficial. The combination of statins with ezetimibe, a newly developed cholesterol-absorption inhibitor, can lead to a further reduction in LDL-C of up to 26%. In this study, we examined the rapidity and intensity of the lipid-lowering effect of ezetimibe co-administered with simvastatin immediately after myocardial infarction. MATERIALS AND METHODS: Sixty patients admitted for acute myocardial infarction were randomized to receive either simvastatin 40 mg (SIMVA), a combination of simvastatin 40 mg and ezetimibe 10 mg (EZE/SIMVA), or no lipid-lowering drugs (NLLD) and had their lipid levels assessed 2, 4 and 7 days later. RESULTS: At baseline, cardiovascular risk factors were similar in all three groups [mean (SD) LDL-C of 141 (36) mg dL(-1)]. At days 2 , 4 and 7 there was no significant change in mean LDL-C levels in the NLLD group (-10%, -6%, and -9%, all P > 0.09), while there were significant reductions with SIMVA (-15%, -27%, and -25%, respectively, all P < 0.001 vs. day 0) and even greater reductions with co-administration of EZE/SIMVA (-27%, -41%, and -51%, respectively, all P < 0.001 vs. day 0). The percentages of patients achieving LDL-C below 70 mg dL(-1) at days 4 and 7 were substantially greater with EZE/SIMVA (45% and 55%, respectively) than with SIMVA (5% and 10%, respectively), while no NLLD patient reached this goal. Triglyceride levels showed a progressive increase in the NLLD group (+45% at day 7, P < 0.05 vs. day 0), no change in the SIMVA group, but a decrease in the EZE/SIMVA group (-17% at day 7, P < 0.05 vs. day 0). No significant difference in HDL-C levels, tolerability, or clinical events was observed between the three groups. CONCLUSIONS: The co-administration of ezetimibe 10 mg with simvastatin 40 mg, by inhibiting cholesterol absorption and production, allowed more patients with acute myocardial infarction to reach LDL-C < or = 70 mg dL(-1) as early as the fourth day of treatment. The effects of such rapid and intense reduction in LDL-C on cardiovascular morbidity and mortality need to be evaluated in future clinical endpoint studies.     

Montelukast modifies simvastatin-induced myopathy and hepatotoxicity

Montelukast (MNK) has prominent anti-inflammatory and antioxidant activities. It can protect the liver in different hepatotoxic models in animals. Simvastatin (SMV) is one of commonly used lipid lowering drugs for treatment of dyslipidemia in order to reduce cardiovascular disease. It has severe side effects such as myopathy and hepatotoxicity. The aim of the present study is to investigate the possible effect of MNK on SMV-induced myopathy and hepatotoxicity. Four groups of male rats: control group which received saline via stomach tube, MNK treated group (received 10 mg/kg/day MNK via stomach tube), SMV treated group (received 30 mg/kg/day SMV via stomach tube), and MNK + SMV (combination) group which received both MNK and SMV. All animals were treated for 14 days before obtaining blood and tissue samples. SMV has both hepatotoxic effects and myopathy. SMV caused a significant increase in myoglobin, creatinine kinase, ALT, AST, ALP, and bilirubin but, it decreased total proteins, globulin and albumin levels. Co-treatment of SMV and MNK increased the antioxidant activity significantly. MNK modifies partially the myopathic changes and hepatotoxic effect of SMV. Co-administration of MNK and SMV decreased their toxic potentials on the liver, skeletal muscles, and kidney. They have antioxidant activities when given together that produce muscle and hepatic protective effects.