Effects Of HMG-CoA Reductase Inhibitors Research Articles

Effects of HMG-CoA reductase inhibitors on learning and memory in the guinea pig

Statins reduce the risk of death from cardiovascular disease in millions of people worldwide. Recent pharmacovigilance data has suggested that people taking statins have an increased risk of psychiatric adverse events such as amnesia and anxiety. This study aimed to investigate the possibility of statin-induced amnesia through animal models of memory and learning. We conducted extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices to examine the effects of acute cholesterol lowering with lipid lowering drugs. We also assessed the effect of six weeks of simvastatin (2mg/kg/d) and atorvastatin (1mg/kg/d) treatment using the Morris water maze. Long Term Potentiation (LTP) was significantly diminished in the presence of 3µM atorvastatin or simvastatin and by the cholesterol sequestering agent methyl-β-cyclodextrin (MBCD). The effects were reversed in the MBCD but not the statin treated slices by the addition of cholesterol. In the water maze, statin treatment did not cause any deficits in the first five days of reference memory testing, but statin treated guinea pigs preformed significantly worse than control animals in a working memory test. The deficits observed in our experiments in water maze performance and hippocampal LTP are suggestive of statin induced changes in hippocampal plasticity. The effects on LTP are independent of cholesterol regulation, and occur at concentrations that may be relevant to clinical use. Our results may help to explain some of the behavioural changes reported in some people after beginning statin treatment.

Rac1-Mediated Effects of HMG-CoA Reductase Inhibitors (Statins) in Cardiovascular Disease

HMG-CoA reductase inhibitors (statins) lower serum cholesterol concentrations and are beneficial in the primary and secondary prevention of coronary heart disease. The positive clinical effects have only partially been reproduced with other lipid-lowering interventions suggesting potential statin effects in addition to cholesterol lowering. In experimental models, direct beneficial cardiovascular effects that are mediated by the inhibition of isoprenoids have been documented, which serve as lipid attachments for intracellular signaling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation. Rac1 GTPase is an established master regulator of cell motility through the cortical actin reorganization and of reactive oxygen species generation through the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Observations in cells, animals, and humans have implicated the activation of Rac1 GTPase as a key component of cardiovascular pathologies, including the endothelial dysfunction, cardiac hypertrophy and fibrosis, atrial fibrillation, stroke, hypertension, and chronic kidney disease. However, the underlying signal transduction remains incompletely understood. Based on the recent advance made in Rac1 research in the cardiovascular system by using mouse models with transgenic overexpression of activated Rac1 or conditional knockout, as well as Rac1-specific small molecule inhibitor NSC 23766, the improved understanding of the Rac1-mediated effects statins may help to identify novel therapeutic targets and strategies.

HMG-CoA-reductase inhibitor co-therapy lowers the risk for incident heart failure in farmorubicin recipients for two cancer locations

Background: Despite the prolonged cancer-related survival in patients (pts) treated with anthracyclines, the treatment related cardiotoxicity remains a major concern. Even though there are some experimental and clinical evidences supporting statins in anthracycline induced cardiotoxicity with doxorubicin, the data in the literature are still poor for farmorubicin, another anthracycline. Aim: The goal of this study was to assess the effect of Continuous Statin Treatment (CST) on new-onset Heart Failure (HF) in pts with breast or gastric cancer treated with farmorubicin. Method: We analysed retrospectively, starting with 01/01/2008, 432 adult pts newly diagnosed with biopsy confirmed breast or gastric cancer who underwent anthracycline based chemotherapy with farmorubicin standard doses. The study group had 144 pts and received CST for usual indications. Their counterparts did not receive CST. The date of the cancer confirmatory diagnosis was considered the study enter date. Demographycally: mean age 53,5±11,2 yrs, female gender predominance 88,2%. The primary outcome was incident HF hospitalization, and the follow-up period 2,55±1,68 yrs. Results: After the propensity matching 2:1, the 144 pts receiving CST were combined with 288 controls. new onset HF was diagnosed in 33 pts, 7 in study group and 26 in their counterparts. The proportion in the two groups were 4,8611, and 9,0277, the dispersion 0,046248, and 0,082127, respectively. Inside the study group, 77 pts received rosuvastatin, 52 pts atorvastatin, and 15 pts other statin. No significant differences were found among various statins; we also did not find any statistical differences between genders. Conclusion: In this study, statin concomitant medication was associated with lower risk for incident HF in pts with breast or gastric cancer treated with farmorubicin. According to our data, this seem to be a class effect of HMG-CoA reductase inhibitors. These findings warrant for further prospective investigation. Since the mechanism of anthracycline cardiotoxicity seems to be correlated with oxygen free radicals, the pleiotropic effects of statins may mitigate cardiotoxicity.

HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation

Recent studies have demonstrated the stimulatory effects of HMG-CoA reductase inhibitors, statins, on IL-1β secretion in monocytes and suggest a crucial role for isoprenoids in the inhibition of caspase-1 activity. In this study, we further elucidated the molecular mechanisms underlying the stimulatory effects of statins on caspase-1. Three commonly recognized mechanistic models for NLRP3 inflammasome activation (i.e., ATP/P2X7/K(+) efflux, ROS production, and lysosomal rupture) were investigated in statin-stimulated human THP-1 monocytes. We found that fluvastatin and lovastatin can synergize with LPS to trigger inflammasome activation. Moreover, statin-induced caspase-1 activation and IL-1β production in LPS-primed THP-1 cells are dependent on GGPP deficiency and P2X7 activation. In particular, increased ATP release accounts for the action of statins in P2X7 activation. We also provide evidence that statin-induced moderate ROS elevation is involved in this event. Moreover, the cathepsin B inhibitor was shown to reduce statin-induced IL-1β secretion. Consistently statins can induce cathepsin B activation and lysosomal rupture, as evidenced by LysoTracker staining. Statins also increase intracellular ATP secretion and IL-1β release in primary human monocytes and murine macrophages. Notably, exogenous ATP-elicited P2X7 activation and consequent IL-1β release, an index of direct NLRP3 inflammasome activation, were not altered by statins. Taken together, statin-induced enhancement of inflammasome activation in monocytes and macrophages covers multiple mechanisms, including increases in ATP release, ROS production, and lysosomal rupture. These data not only shed new insight into isoprenylation-dependent regulation of caspase-1 but also unmask mechanisms for statin-elicited inflammasome activation.

Proteomic analysis of endothelial cell secretome: A means of studying the pleiotropic effects of Hmg-CoA reductase inhibitors

The clinical benefits of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are closely related to their cholesterol-lowering properties. However, the inhibition of HMG-CoA reductase may also lead to pleiotropic effects due to the ability to inhibit the synthesis of non-steroidal isoprenoid compounds, thus exerting extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. To identify new drug targets by means of which statins can promote some of their beneficial effects we used a global proteomic approach to analyse the secretome of endothelial cells, a major class of proteins that control a multitude of biological and physiological processes. Differentially expressed proteins were identified using a data-independent, label-free, mass spectrometry-based method. A total of 273 proteins were identified, including 112 that were differentially expressed: 29 uniquely expressed in control cells, 14 uniquely expressed in statin-treated cells, 51 down-regulated by statin, and 18 up-regulated by statin. Gene ontology analysis revealed modulated biological processes related to proteolysis, cellular component organisation and biogenesis, and response to stress. The findings were validated by biochemical assays, thus confirming the effectiveness of our proteomic approach. In conclusion, this study underlines the role of proteomics for the discovery of novel and unpredictable targets of statins.

The Effect of HMG-CoA Reductase Inhibitor on Insulin Resistance in Patients Undergoing Peritoneal Dialysis

Insulin resistance is associated with the progression of atherosclerosis and is reported to predict cardiovascular mortality in patients with end-stage renal disease (ESRD). Although statins exert pleiotropic effects, it is uncertain whether statin therapy improves insulin resistance in these patients. In this prospective randomized controlled trial, we aimed to evaluate the effects of statin on insulin resistance among 70 patients undergoing peritoneal dialysis (PD). Patients were randomized into a statin group (n = 35) or a control group (n = 35). The statin group received 10 mg per day of rosuvastatin for 6 months. We determined insulin resistance by homeostatic model assessment of insulin resistance (HOMA-IR) index. Serum concentrations of adipokines such as adiponectin, leptin, and resistin were measured using enzyme-linked immunosorbent (ELISA) assay. As inflammatory markers, high sensitive C-reactive protein (hsCRP) and interleukin-6 were also measured. There were no significant differences in baseline characteristics between the two groups. Compared to baseline value, statin treatment significantly decreased HOMA-IR index from 2.37 ± 1.08 to 2.05 ± 0.82 (P = 0.014). There was a concordant decrease in hsCRP levels in the statin group (2.05 ± 1.57 to 1.21 ± 0.84 mg/L, P < 0.001), but such improvements were not observed in the control group. When between-group differences in these parameters were compared, hsCRP levels were more decreased in the statin group than in the control group (P = 0.021 for between-group difference), whereas HOMA-IR index was not (P = 0.189 for between-group difference). During this period, statin treatment did not result in the improved adipokine profiles. This study showed that statin therapy failed to improve insulin resistance in PD patients despite a significant decline in hsCRP levels after statin treatment. Our finding suggests that reducing inflammation by statin is of limited help to fully attenuate insulin resistance in these patients.

The Effect of HMG-CoA Reductase Inhibitors on Cognition in Patients With Alzheimer's Dementia: A Prospective Withdrawal and Rechallenge Pilot Study

BackgroundStatins are well-known for their cardiovascular benefits. However, the cognitive effects of statins are not well understood. We hypothesized that individuals with preexisting dementia would be more vulnerable to statin-related cognitive effects. ObjectiveThe aim of this study was to evaluate the impact on cognition of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor (statin) discontinuation and rechallenge in individuals with Alzheimer's dementia (AD) on statins at baseline. MethodsA 12-week prospective, open-label study was conducted in a geriatric clinic setting. Eighteen older subjects underwent a 6-week withdrawal phase of statins followed by a 6-week rechallenge. The primary outcome measure was cognition, measured by the Mini-Mental State Examination (MMSE); secondary outcome measures were the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery, Activities of Daily Living (ADL) scale, Instrumental ADL (IADL) scale, and fasting cholesterol. The change in outcome measures was assessed using repeated-measures ANOVA and paired t tests. ResultsAt the end of the intervention, there was a significant difference across time for MMSE score (P = 0.018), and total cholesterol (P = 0.0002) and a trend toward change across time for ADL (P = 0.07) and IADL (P = 0.06) scale scores. Further analyses using paired t tests indicated improvement in MMSE scores (Δ1.9 [3.0], P = 0.014) with discontinuation of statins and a decrease in MMSE scores (Δ1.9 [2.7], P = 0.007) after rechallenge. Total cholesterol increased with statin discontinuation (P = 0.0003) and decreased with rechallenge (P = 0.0007). The CERAD score did not show a change across time (P = 0.31). There was a trend toward improvement in ADL (P = 0.07) and IADL (P = 0.06) scale scores with discontinuation of statins, but no change with rechallenge. ConclusionsThis pilot study found an improvement in cognition with discontinuation of statins and worsening with rechallenge. Statins may adversely affect cognition in patients with dementia.

Neuroprotective potential of atorvastatin and simvastatin (HMG-CoA reductase inhibitors) against 6-hydroxydopamine (6-OHDA) induced Parkinson-like symptoms

Neuro-inflammation and oxidative stress plays a key role in the pathophysiology of Parkinson's disease (PD). Studies demonstrated that neuro-inflammation and associated infiltration of inflammatory cells into central nervous system are inhibited by 3-hydroxy-3-methyl glutaryl co-enzyme A (HMG-CoA) reductase inhibitors. Based on these experimental evidences, the present study has been designed to evaluate the neuroprotective effect of HMG-CoA reductase inhibitors (atorvastatin and simvastatin) against 6-hydroxydopamine (6-OHDA) induced unilateral lesion model of PD. In the present study, the animals were divided into nine groups (n=15 per group). Group I: Naive (without treatment); Group II: Sham (surgery performed, vehicle administered); Group III: Atorvastatin (20mg/kg); Group IV: Simvastatin (30mg/kg); Group V: Control [Intrastriatal 6-OHDA (20μg; single unilateral injection)]; Groups VI and VII: 6-OHDA (20μg)+atorvastatin (10mg/kg and 20mg/kg) respectively; Groups VIII and IX: 6-OHDA (20μg)+simvastatin (15mg/kg and 30mg/kg) respectively. Intrastriatal administration of 6-OHDA (20μg; 4μl of 5μg/μl) significantly caused impairment in body weight, locomotor activity, rota-rod performance, oxidative defense and mitochondrial enzyme complex activity, and increase in the inflammatory cytokine levels (TNF-α and IL-6) as compared to naive animals. Atorvastatin (20mg/kg) and simvastatin (30mg/kg) drug treatment significantly improved these behavioral and biochemical alterations restored mitochondrial enzyme complex activities and attenuated neuroinflammatory markers in 6-OHDA (20μg) treated animals as compared to control group. The findings of the present study demonstrate the neuroprotective potential of statins in experimental model of 6-OHDA induced Parkinson like symptoms.

Effect of HMG‐CoA reductase inhibitors on antimicrobial susceptibilities for Gram‐Negative rods

Epidemiologic evidence suggests a beneficial effect of HMG-CoA reductase inhibitors (statins) in sepsis, and in-vitro data exist for antimicrobial activity of statins against some bacteria and fungi. We examined whether statin exposure at physiologic concentrations enhances activity of selected antimicrobials against Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Broth microdilution was performed with and without dose-ranging concentrations of lovastatin, fluvastatin, atorvastatin, pravastatin and simvastatin. No effects on antimicrobial activity were demonstrated.

Sa1206 Effects of HMG-CoA Reductase Inhibitor (Statin) on Apoptosis in Cultured Bile Duct Cancer Cells

Sa1206 Effects of HMG-CoA Reductase Inhibitor (Statin) on Apoptosis in Cultured Bile Duct Cancer Cells

Cancer in cardiovascular drug trials and vice versa: a personal perspective

Acknowledging uncertainties and balancing the opportunity for benefit with the offsetting potential to harm are integral concepts for clinical decision-making. Caregivers consciously risk profile (stratify) their patient to try to fit best currently available observational and clinical trial data to formulate a particular recommendation for each unique patient. Advice to adopt prudent lifestyle approaches, such as avoidance of smoking, maintaining adequate activity levels, and adhering to a nutritious diet, have such a favourable benefit/risk ratio that they have become fundamental tenets of cardiovascular preventive care. On the other hand, recommendations for the use of pharmacologic therapies in an effort to improve prognosis requires careful consideration of possible adverse consequences in relation to potential benefits. The fundamental principle of ‘Primum non nocere’, above all first, do no harm, rightfully dominates most clinicians' therapeutic decision making. To initiate and maintain a pharmaceutical agent or recommend a procedure, the physician, patient, and even the payers must be adequately persuaded that in the long term, the risk/benefit considerations favour the intervention. In cardiovascular medicine, strong and consistent information from both pioneering epidemiologic and clinical trial data have coalesced to generate convincing, indeed, compelling rationale for the use of pharmacologic agents in individuals with hypertension to lower arterial blood pressure in order to reduce their risk for subsequent major cardiovascular events.1–3 Similarly, there is consistent convincing data demonstrating the effectiveness of HMG-CoA reductase inhibitors (statins) in lowering cardiovascular event rates in both secondary and in a large segment of the primary prevention populations.4 Pharmacologic agents in these categories have achieved privileged regulatory and clinical usage status to be administered to asymptomatic individuals for the purpose of reducing cardiovascular event rates. At this elite level, in addition to sufficient safety experience, a particular agent must also have excellent tolerability and often even …

Combination therapy with an angiotensin II receptor blocker and an HMG-CoA reductase inhibitor in experimental subtotal nephrectomy

Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease. Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys. In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries. In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.

Oral Abstract Sessions: Young Investigator Award session * Thursday 8 December 2011, 12:45-13:45 * Location: Pecs

Oral Abstract Sessions: Young Investigator Award session * Thursday 8 December 2011, 12:45-13:45 * Location: Pecs

Abstract 9653: Crucial Role of SmgGDS in the Molecular Mechanisms of the Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Background: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. We have previously demonstrated that the pleiotropic effects of low-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway. However, the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by low-dose statins remain to be elucidated. Methods and Results: We tested our hypothesis that the small GTP-binding protein dissociation stimulator (SmgGDS) plays an important role in this mechanism. In cultured human umbilical venous endothelial cells (HUVEC), statins (atorvastatin, 10 to 30 μ mol/L and pitavastatin, 1 to 10 μ mol/L) concentration-dependently increased SmgGDS expression and decreased nuclear Rac1 after 24h treatment (both P&lt;0.05, n=3 each). Intranuclear degradation of Rac1 was reduced by the proteasome inhibitor, MG-132 (P&lt;0.01, n=3). When SmgGDS was knockdown by its siRNA in HUVEC, statins were no longer able to induce Rac1 degradation (P&lt;0.01, n=3) or to inhibit angiotensin II-induced production of reactive oxygen species (ROS) (P&lt;0.01, n=8). In littermate mice, the protective effects of statins (atorvastatin, 10 mg/kg/day for 2 weeks and pravastatin, 50 mg/kg/day for 2 weeks) against AngII-induced cardiovascular hypertrophy and diastolic dysfunction were noted (AngII group vs. statin groups, P&lt;0.01, n=10), whereas in SmgGDS-deficient mice, the protective effects of statins were absent (n=10). Finally, in normal healthy volunteers, a low-dose statin (pravastatin; 10 mg/day for 4 weeks) significantly increased SmgGDS expression (P&lt;0.01, n=19). A significant negative correlation was noted between the extent of SmgGDS expression and oxidative stress markers (MDA-LDL-cholesterol, R=0.45; 8-OHdG, R=0.40), whereas no significant correlation was noted with total or LDL-cholesterol. Conclusions: These results provide the first direct evidence that SmgGDS plays a crucial role in the molecular mechanisms of the pleiotropic effects of statins through enhancement of intranuclear Rac1 degradation in animals and humans.

Low-Dose Pravastatin and Age-Related Differences in Risk Factors for Cardiovascular Disease in Hypercholesterolaemic Japanese

Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment. The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease. To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45-49, 50-54, 55-59, 60-64 and ≥65 years. The relationship between pravastatin (10-20 mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model. The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10-20 mg/day) reduced the risk of CVD by about 30-40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged ≥65 vs ≥45 years). A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors. ClinicalTrials.gov Identifier: NCT00211705.

Effects of HMG-CoA Reductase Inhibitors on the Pharmacokinetics of Losartan and Its Main Metabolite EXP-3174 in Rats: Possible Role of CYP3A4 and P-gp Inhibition by HMG-CoA Reductase Inhibitors

The present study was designed to investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG-CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC₅₀ values of 48.0, 14.1 and 3.10 µmol/l, respectively. Simvastatin (1–10 µmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. The area under the plasma concentration-time curve (AUC_0–∞) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin.

Apposite Insulin-like Growth Factor (IGF) Receptor Glycosylation Is Critical to the Maintenance of Vascular Smooth Muscle Phenotype in the Presence of Factors Promoting Osteogenic Differentiation and Mineralization

Vascular calcification is strongly linked with increased morbidity and mortality from cardiovascular disease. Vascular calcification is an active cell-mediated process that involves the differentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. Several inhibitors of this process have been identified, including insulin-like growth factor-I (IGF-I). In this study, we examined the role of the IGF receptor (IGFR) and the importance of IGFR glycosylation in the maintenance of the VSMC phenotype in the face of factors known to promote osteogenic conversion. IGF-I (25 ng/ml) significantly protected VSMCs from β-glycerophosphate-induced osteogenic differentiation (p < 0.005) and mineral deposition (p < 0.01). Mevalonic acid depletion (induced by 100 nm cerivastatin) significantly inhibited these IGF protective effects (p < 0.01). Mevalonic acid depletion impaired IGFR processing, decreased the expression of mature IGFRs at the cell surface, and inhibited the downstream activation of Akt and MAPK. Inhibitors of N-linked glycosylation (tunicamycin, deoxymannojirimycin, and deoxynojirimycin) also markedly attenuated the inhibitory effect of IGF-I on β-glycerophosphate-induced mineralization (p < 0.05) and activation of Akt and MAPK. These results demonstrate that alterations in the glycosylation of the IGFR disrupt the ability of IGF-I to protect against the osteogenic differentiation and mineralization of VSMCs by several interrelated mechanisms: decreased IGFR processing, reduced IGFR cell-surface expression, and reduced downstream signaling via the Akt and MAPK pathways. IGF-I thus occupies a critical position in the maintenance of normal VSMC phenotype and protection from factors known to stimulate vascular calcification.

Regulation mechanism of ABCA1 expression by statins in hepatocytes

ATP-binding cassette transporter A1 (ABCA1) is predicted to be involved in the control of apolipoprotein AI-mediated cholesterol efflux: biosynthesis of high-density lipoprotein (HDL). However, the effects of HMG-CoA reductase inhibitors (statins) on ABCA1 in the liver and the precise mechanisms of their actions have been obscure. The aims of this study were to determine whether statins (atorvastatin (Ato) and pitavastatin (Pit)) affect hepatic ABCA1 expression and to clarify the mechanisms of their actions using HepG2 cells and the rat liver. We examined alterations in mRNA and protein levels of ABCA1 and peroxisome proliferator-activated receptors (PPARs) by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. In vitro and in vivo studies suggested that Pit increases ABCA1 mRNA level, but not Ato. Pit greatly increased Abca1 mRNA level and also increased the amount of plasma HDL and the mRNA level of PPARα. Clofibrate (PPARα agonist) increased ABCA1 expression in HepG2 cells and rat primary hepatocytes more than did PPAR β/δ and γ agonists. Pit-induced ABCA1 expression alteration was blocked by GW6471 (PPARα antagonist) and by PPARα knockdown. In this study, we demonstrated that Pit affect ABCA1 expression via PPARα in hepatocytes. The strategy to target a PPARα agonist in the liver can lead to increases in ABCA1 expression and HDL level.

Statyny i astma

Statins are drugs widely used in the treatment of hyperlipidemia and cardiovascular diseases. They decrease cholesterol synthesis by inhibiting 3-hydroxy-methylglutaryl reductase of coenzyme A (HMG-CoA). It was shown that statins are characterized by a wider spectrum of activity, which was attributed as an extralipid (pleiotropic) one. Although benefits of HMG-CoA reductase inhibitors have been proven in the treatment of cardiovascular diseases, there are attempts to use them in other fields of medicine, such as neurology and rheumatology. At present, anti-inflammatory and immunomodulatory effects of HMG-CoA reductase inhibitors are being particularly examined. Based on the observation mentioned above, the use of statins in allergology has also been attempted. The paper presents selected aspects of statins’ effects on immunological reactions and the inflammatory process, pointing to the possibility of statin use in the treatment of asthma.

Combined vascular effects of HMG-CoA reductase inhibitor and angiotensin receptor blocker in non-diabetic patients undergoing peritoneal dialysis

Statins and angiotensin receptor blockers (ARBs) are known to improve vascular dysfunction in patients with chronic kidney disease. However, these effects have been inconsistent in dialysis patients. Moreover, it is currently unknown whether adding statins to ARBs improves vascular dysfunction better than ARB monotherapy in these patients. We conducted a prospective open randomized trial to investigate the effects of statin add-on to ARB on vascular protection in 124 nondiabetic patients undergoing peritoneal dialysis (PD). Initially, all patients received 80 mg/day of valsartan for 6 months. Excluding 10 patients who dropped out during this period, patients were randomly assigned to continue ARB treatment alone (n = 57) or to receive 10 mg/day of rosuvastatin (n = 57) added to ARB for the next 6 months. To assess vascular function, endothelium-dependent vasodilation and arterial stiffness were determined by brachial artery flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV), respectively. Compared to baseline values, ARB treatment for the first 6 months significantly improved FMD% (2.97 ± 2.64 to 3.57 ± 2.58 %, P < 0.001). In addition, there was a small but significant decrease in baPWV during this period (1691.5 ± 276.3 to 1635.0 ± 278.6 cm/s, P = 0.048). After randomization, add-on treatment further improved FMD% (3.57 ± 2.73 to 4.24 ± 2.77 %, P = 0.003), whereas ARB monotherapy did not (P = 0.02 for between-group difference). Further slight improvement in baPWV (1617.0 ± 280.9 to 1528.9 ± 266.8 cm/s, P = 0.021) was observed only in the combined treatment group (P = 0.28 for between-group difference). Adding a statin to the ARB was of some help in improving vascular dysfunction more effectively than ARB monotherapy in nondiabetic PD patients. However, whether such limited improvements can lead to better clinical outcomes requires further investigation.