Atorvastatin Pretreatment Research Articles

Developing a Biomimetic 3D Neointimal Layer as a Prothrombotic Substrate for a Humanized In Vitro Model of Atherothrombosis.

Acute cardiovascular events result from clots caused by the rupture and erosion of atherosclerotic plaques. This paper aimed to produce a functional biomimetic hydrogel of the neointimal layer of the atherosclerotic plaque that can support thrombogenesis upon exposure to human blood. A biomimetic hydrogel of the neointima was produced by culturing THP-1-derived foam cells within 3D collagen hydrogels in the presence or absence of atorvastatin. Prothrombin time and platelet aggregation onset were measured after exposure of the neointimal models to platelet-poor plasma and washed platelet suspensions prepared from blood of healthy, medication-free volunteers. Activity of the extrinsic coagulation pathway was measured using the fluorogenic substrate SN-17. Foam cell formation was observed following preincubation of the neointimal biomimetic hydrogels with oxidized LDL, and this was inhibited by pretreatment with atorvastatin. The neointimal biomimetic hydrogel was able to trigger platelet aggregation and blood coagulation upon exposure to human blood products. Atorvastatin pretreatment of the neointimal biomimetic layer significantly reduced its pro-aggregatory and pro-coagulant properties. In the future, this 3D neointimal biomimetic hydrogel can be incorporated as an additional layer within our current thrombus-on-a-chip model to permit the study of atherosclerosis development and the screening of anti-thrombotic drugs as an alternative to current animal models.

High-dose atorvastatin reduces oxidative stress of ischemia/reperfusion injury after isogeneic kidney transplantation in rats: in vivo, preclinical, case–control, open-label study

BackgroundRenal ischemia/reperfusion injury is an unavoidable event in transplantation in which free radical-mediated injury determines release of pro-inflammatory cytokines and activation of innate immunity. In addition to their cholesterol-lowering action, statins have shown dose-dependent pleiotropic effects on inflammatory pathways and oxidative stress. We investigated the effects of high-dose atorvastatin (atorvastatin 40 mg/kg) in preventing ischemia/reperfusion injury in an animal model of kidney transplant.MethodsForty female rats underwent left nephrectomy and orthotopic autotransplantation. Animals were divided in four groups: A = Transplant only; B = high-dose atorvastatin + Transplant; C = right nephrectomy + Transplant; D = high-dose atorvastatin + right nephrectomy + Transplant. Bilateral nephrectomy was performed 24 h post-transplant. Oxidative stress was assessed measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activity on renal tissue; ischemia/reperfusion injury was also evaluated by histology. Donor pre-treatment with high-dose atorvastatin improved oxidative stress.ResultsMDA levels were lower in group B versus A (p = 0.002) and D (p = 0.004). High-dose atorvastatin pre-treated rats displayed higher GPx activity in group B versus A (p = 0.009) and D (p = 0.005). SOD scavenger activity was also higher in group B versus A (p < 0.001) D (p < 0.001) and C (p = 0.003). MPO activity was lower in group B versus A (p = 0.02), C (p = 0.007) and D (p = 0.03). Histology revealed significantly lower rate of intratubular casts and luminal congestion in Group D versus C (p = 0.02 and p = 0.008, respectively).ConclusionsHigh-dose atorvastatin pre-treatment reduces oxidative stress and inflammation in a model of kidney transplant in the rat.

Atorvastatin-mediated inhibition of prenylation of Rab27b and Rap1a in platelets attenuates their prothrombotic capacity and modulates clot structure

Statins inhibit the mevalonate pathway by impairing protein prenylation via depletion of lipid geranylgeranyl diphosphate (GGPP). Rab27b and Rap1a are small GTPase proteins involved in dense granule secretion, platelet activation, and regulation. We analyzed the impact of statins on prenylation of Rab27b and Rap1a in platelets and the downstream effects on fibrin clot properties. Whole blood thromboelastography revealed that atorvastatin (ATV) delayed clot formation time (P < .005) and attenuated clot firmness (P < .005). ATV pre-treatment inhibited platelet aggregation and clot retraction. Binding of fibrinogen and P-selectin exposure on stimulated platelets was significantly lower following pre-treatment with ATV (P < .05). Confocal microscopy revealed that ATV significantly altered the structure of platelet-rich plasma clots, consistent with the reduced fibrinogen binding. ATV enhanced lysis of Chandler model thrombi 1.4-fold versus control (P < .05). Western blotting revealed that ATV induced a dose-dependent accumulation of unprenylated Rab27b and Rap1a in the platelet membrane. ATV dose-dependently inhibited ADP release from activated platelets. Exogenous GGPP rescued the prenylation of Rab27b and Rap1a, and partially restored the ADP release defect, suggesting these changes arise from reduced prenylation of Rab27b. These data demonstrate that statins attenuate platelet aggregation, degranulation, and binding of fibrinogen thereby having a significant impact on clot contraction and structure.

Atorvastatin prevents cadmium-induced renal toxicity in a rat model.

In many industrial processes, worker exposure to cadmium causes kidney damage; thus, protection against cadmium toxicity is important in workplace health. Cadmium toxicity involves oxidative stress by increasing the levels of reactive oxygen species. Statins have shown antioxidant effects that might prevent this increase in oxidative stress. We investigated the potential effects of atorvastatin pretreatment in protecting experimental rats against kidney toxicity caused by cadmium. Experiments were performed on 56 adult male Wistar rats (200 ± 20g), randomly assigned to eight groups. Atorvastatin was administered by oral gavage for 15days at 20mg/kg/day, starting 7days before cadmium chloride intra-peritoneal administration (at 1, 2, and 3mg/kg) for 8days. On day 16, blood samples were collected, and kidneys were excised to evaluate the biochemical and histopathological changes. Cadmium chloride significantly increased malondialdehyde, serum creatinine, blood urea nitrogen, and decreased superoxide dismutase, glutathione, and glutathione peroxidase levels. Pre-administration of rats with atorvastatin at a dose of 20mg/kg decreased blood urea nitrogen, creatinine, and lipid peroxidation, increased the activities of antioxidant enzymes, and prevented changes in physiological variables compared with animals that were not pretreated. Atorvastatin pretreatment prevented kidney damage following exposure to toxic doses of cadmium. In conclusion, atorvastatin pretreatment in rats with cadmium chloride-induced kidney toxicity could reduce oxidative stress by changing biochemical functions and thereby decreasing damage to kidney tissue.

The preventive effects of different doses of atorvastatin on contrast‐induced acute kidney injury after CT perfusion

BackgroundContrast‐induced acute kidney injury (CI‐AKI) is a severe complication among patients receiving intravascular contrast media. The purpose of this study was to investigate the preventive effects of pretreatment of atorvastatin at intensive doses on CI‐AKI after computed tomography (CT) perfusion.MethodsThe levels of serum creatinine (SCR), blood urea nitrogen (BUN), Cystatin C (CysC), estimated glomerular filtration rate (eGFR), high‐sensitivity C‐reactive protein (hs‐CRP), and interleukin‐6 (IL‐6) in patients were compared between the observation group receiving 40 mg/kg atorvastatin and the control group receiving 20 mg/kg atorvastatin before and 72 h after CT examination. In addition, the incidence of CI‐AKI was recorded.ResultsCompared with the control group, the incidence of renal injury in the observation group was significantly reduced, from 8% to 2% (χ 2 = 6.62, p = 0.010). In addition, there was no notable difference in the levels of Scr, BUN, CysC, hs‐CRP, and IL‐6 before CT examination between two groups (p > 0.05). The levels of SCR, BUN, CysC, hs‐CRP, and IL‐6 were increased, while the levels of eGFR were decreased in the control group at 72 h after CT examination (p < 0.05). At 72 h after CT enhancement, the levels of BUN, CysC, and hs‐CRP were prominently increased in the observation group (p < 0.05), while SCR, eGFR, and IL‐6 did not change (p > 0.05). Compared with the control group, the levels of SCR, BUN, CysC, eGFR, hs‐CRP, and IL‐6 in the observation group were significantly decreased at 72 h after CT examination (p < 0.05).ConclusionIntensive dose of atorvastatin pretreatment can prevent CI‐AKI undergoing CT perfusion through lowering inflammation as well as renal function indexes SCR, CysC, BUN, and eGFR.

Atorvastatin Exerts Protective Effect on Cardiopulmonary Bypass Induced Renal Injury in Rats via PPAR-γ.

To investigate the protective effect and possible mechanism of atorvastatin pretreatment on renal function after cardiopulmonary bypass (CPB) in rats. Twenty-four adult male Sprague-Dawley (SD) rats randomly were divided into three groups: Sham operation group, CPB group, and administration group (N = 8 in each group). The caudal artery and right jugular vein were used to establish the CPB circuit for the CPB and administration groups. Drugs were administered by oral gavage one week before the operation. All rats were executed for succeeding experiments 72h after the operation. Plasma levels of creatinine (Cre) and IL-8 at different time points and levels of TNF-α and MPO in renal tissue were detected by ELISA. Renal pathological changes were observed by HE staining. PPAR-γ expression was determined by immunohistochemistry and western blot. All rats survived the whole process without incident. Renal function of rats undergoing CPB was impaired to varying degrees based on the plasma Cre concentration, and atorvastatin pretreatment alleviated this effect. The concentrations of six inflammatory cytokines (IL-1β, IL-6,IL-8, IFN-γ,TNF-α, and MPO) were significantly elevated after CPB procedure, while atorvastatin pretreatment ameliorated the inflammatory condition caused by CPB. Further analysis showed that in both HK-2 cells and renal tissues, atorvastatin promoted the expression of PPAR-γ. Atorvastatin pretreatment exerted protective effect on CPB-associated kidney injury and inflammation in rats. The activation of PPAR-γ may contribute to the protective effect of Atorvastatin.

Cardioprotective Effect of Pretreatment with A Single High-Dose Atorvastatin via Regulating Myocardial Uncoupling Protein 3 in a Rat Ischemia/Reperfusion Model

Objective: Since ischemia/reperfusion (I/R) can cause malignant arrhythmia, we explored the cardioprotective effect of pretreatment with a single and large dose of atorvastatin in the SD rat model. Methods: Rats were distributed into atorvastatin (Ator), I/R model and sham groups (n = 8/group) by random number table method. In Ator group, atorvastatin was gavaged with a single dose (80 mg/kg) 12 h before I/R. The heart was treated with ischemia for 30 min and then reperfusion for 2 h. Results: Myocardial infarct area was induced by I/R when compared with Sham group. Compared with I/R group, the pretreatment of atorvastatin significantly reduced area at risk/left ventricle (40.78 ± 1.39% vs. 46.76 ± 1.42%, p &lt; 0.01), infarct area/area at risk (21.47 ± 1.65% vs. 29.16 ± 1.21%, p &lt; 0.01), and lactate dehydrogenase activity (3056.17 ± 136.22 RFU vs. 3864.15 ± 162.92 RFU, p &lt; 0.05). I/R induced uncoupling protein 3 (UCP3) in transcriptional and translational levels, but atorvastatin significantly increased the UCP3 expression when compared with I/R group, 1.91 ± 0.42 vs. 1.42 ± 0.21 fold (p &lt; 0.05) in mRNA levels measured by RT-PCR and 2.07 ± 0.18 versus 1.45 ± 0.23 fold in protein levels by Western blots. Conclusion: A single high-dose atorvastatin pretreatment 12 h before I/R reduces the infarct area in I/R model in rats. The cardioprotection may be via regulating myocardial UCP3.

Atorvastatin Pretreatment Ameliorates Mesenchymal Stem Cell Migration through miR-146a/CXCR4 Signaling.

We previously found that atorvastatin (ATV) enhanced mesenchymal stem cells (MSCs) migration, by a yet unknown mechanism. CXC chemokine receptor 4 (CXCR4) is critical to cell migration and regulated by microRNA-146a (miR-146a). Therefore, this study aimed to assess whether ATV ameliorates MSCs migration through miR-146a/CXCR4 signaling. Expression of CXCR4 was evaluated by flow cytometry. Expression of miR-146a was examined by reverse transcription-quantitative polymerase chain reaction. A transwell system was used to assess the migration ability of MSCs. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). Mimics of miR-146a were used in vitro, and miR-146a overexpression lentivirus was used in vivo, to assess the role of miR-146a in the migration ability of MSCs. The results showed that ATV pretreatment in vitro upregulated CXCR4 and induced MSCs migration. In addition, flow cytometry demonstrated that miR-146a mimics suppressed CXCR4, and ATV pretreatment no longer ameliorated MSCs migration because of decreased CXCR4. In the AMI model, miR-146a-overexpressing MSCs increased infarct size and fibrosis. The miR-146a/CXCR4 signaling pathway contributes to MSCs migration and homing induced by ATV pretreatment. miR-146a may be a novel therapeutic target for stimulating MSCs migration to the ischemic tissue for improved repair.

Exogenous Vitamins K Exert Anti-Inflammatory Effects Dissociated from Their Role as Substrates for Synthesis of Endogenous MK-4 in Murine Macrophages Cell Line.

Vitamins K exert a range of activities that extend far beyond coagulation and include anti-inflammatory effects, but the mechanisms involved in anti-inflammatory action remain unclear. In the present study, we showed that various forms of exogenous vitamins—K1, K3, K2 (MK-4, MK-5, MK-6 and MK-7)—regulated a wide scope of inflammatory pathways in murine macrophages in vitro, including NOS-2, COX-2, cytokines and MMPs. Moreover, we demonstrated for the first time that macrophages are able to synthesise endogenous MK-4 on their own. Vitamins with shorter isoprenoid chains—K1, K3 and MK-5—exhibited stronger anti-inflammatory potential than vitamins with longer isoprenoid chains (MK-6 and MK-7) and simultaneously were preferably used as a substrate for MK-4 endogenous production. Most interesting, atorvastatin pretreatment inhibited endogenous MK-4 production but had no impact on the anti-inflammatory activity of vitamins K. In summary, our results demonstrate that macrophages are able to synthesise endogenous MK-4 using exogenous vitamins K, and statin inhibits this process. However, the anti-inflammatory effect of exogenous vitamins K was independent of endogenous MK-4 synthesis.

Evaluation of high-dose atorvastatin pretreatment influence in patients preconditioning of post coronary artery bypass graft surgery: A prospective triple blind randomized clinical trial.

Context:Atorvastatin is considered as lipid reductive drugs with anti-inflammatory and pleotherapic effects in coronary artery bypass graph (CABG).Aim:This study is conducted to evaluate the effects of atorvastatin in CABG.Setting and Design:Patients with a coronary bypass graph procedure in Nemazee hospital in Shiraz were divided into two 50-groups receiving high-dose (80 mg) and low-dose (20 mg) atorvastatin.Materials and Methods:Troponin I, creatinine kinase-MB (CK-MB), atrial fibrillation (AF) after CABG, duration of mechanical ventilation, inotrope duration of consumption, blood sugar profile, liver and renal function, death during 30 days of CABG, MACE (major advance cardiac events) during admission in ICU, and 1 month follow up were surveyed.Statistical Analysis:Collected data were analyzed by independent and paired t-test and Chi square.Results:AST was increased, ALT, ALK-P after CABG were decreased, and urine volume in the second day of admission in ICU was increased in the high-dose group. There was an increase and following decrease in blood sugar of patients in the high-dose after CABG. An inflammatory marker after CABG was raised in both groups, ck-mb had an increase, and then followed by a reduction. Troporin had no significant differences between groups. Patients with high-dose atorvastatin had better glomerular filtration rate and renal performance. Along with decreasing AF in the case group, hemodynamics' disorder reduced and there was less bleeding.Conclusion:According to the above, it seems that a short-time prescription of high dose of atorvastatin in CABG can lead to better renal function, decreasing of arrhythmia and AF.

Pretreatment with atorvastatin ameliorates cobra venom factor-induced acute lung inflammation in mice

BackgroundThe complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study.MethodsATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting.ResultsThe lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung.ConclusionThese findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

Effects of atorvastatin on pharmacokinetics of amlodipine in rats and its potential mechanism

Atorvastatin combined with amlodipine (ALDP) can efficiently treat the hypertension with coronary heart disease. However, the drug-drug interaction between atorvastatin and ALDP are still unknown.This study investigates the effects of atorvastatin on the pharmacokinetics of ALDP in rats and clarifies its main mechanism.The pharmacokinetic profiles of oral administration of ALDP (1 mg/kg) in Sprague-Dawley rats, with or without pretreatment of atorvastatin (1.5 mg/kg/d for 7 d) were investigated. The effects of atorvastatin on the metabolism of ALDP were also investigated using rat liver microsomes.The results showed that atorvastatin could significantly increase the peak plasma concentration (from 18.28 ± 2.65 to 24.13 ± 1.96 ng/mL) and decrease the oral clearance (from 4.57 ± 1.15 to 1.79 ± 0.28 L/h/kg) of ALDP. In the rat liver microsome systems, the intrinsic clearance rate of ALDP was decreased by the pretreatment with atorvastatin (39.26 ± 2.1 vs. 33.24 ± 3.3 μL/min/mg protein).Those results indicated that atorvastatin could significantly affect the pharmacokinetic of ALDP, via inhibiting the metabolism of ALDP in rats.

P825Long-term clinical benefit of atorvastatin pretreatment before primary percutaneous coronary intervention in patients with STEMI: a multi-center propensity score-matched study

Abstract Aims We aim to investigate the effect of single dose of statin pretreatment prior to primary Percutaneous Coronary Intervention (PCI) on long-term clinical outcomes in patients with ST-elevation Myocardial Infarction (STEMI). Methods Using data from China Acute myocardial Infarction (CAMI) registry, we compared the outcome in STEMI patients with vs without atorvastation pretreatment prior to primary PCI. The primary endpoint was the composite outcome of all-cause mortality, non-fatal MI or stroke events during follow-up. Propensity-score (PS) matching was used to assemble a cohort of patients with similar baseline characteristics. All patients were followed till 24 months since baseline. Results Of all 3772 patients who met our inclusion criteria at 108 hospitals in China, 3288 patients (1644 patients in each arm) were included in our PS-matched cohort. In the PS-match cohort, overall 144 (8.65%) and 113 (6.79%) patients in the control group and pretreatment group had the primary endpoint respectively (p=0.048). The estimated HRs were 0.78 (95% CI: 0.606–0.997, p=0.046) in the unadjusted model and 0.76 (95% CI: 0.596–0.984, p=0.032) in the adjusted model (Figure). The HRs were broadly similar for the pretreatment dosage of 40 mg or 80 mg (0.78 vs 0.77, p=0.75). The HRs were even stronger in patients with single-vessel only than multi-vessel coronary artery disease (0.31 vs 0.75, p=0.014). Conclusion Among Chinese patients with STEMI, atorvastatin pretreatment before primary PCI may have better long-term composite outcome of all-cause mortality, non-fatal MI, or stroke events. Acknowledgement/Funding CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-009)

Prophylactic atorvastatin prior to intra-arterial administration of iodinated contrast media for prevention of contrast-induced acute kidney injury: A meta-analysis of randomized trial data .

The efficacy of high-dose atorvastatin pretreatment in reducing the incidence of contrast-induced nephropathy in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) has been examined in some randomized studies. However, the results across the trials remain controversial. This study sought to perform a meta-analysis to evaluate the effect of high-dose atorvastatin in the prevention of contrast-induced nephropathy (CIN) while undergoing CAG or PCI. Comprehensive literature searches for randomized controlled trials (RCTs) comparing high-dose atorvastatin vs. low-dose statin or placebo pretreatment for prevention of contrast-induced acute kidney injury in patients undergoing CAG were performed using PubMed, Embase, and the Cochrane library updated to June 2017. The primary outcome was the incidence of CIN. A total of 11 RCTs were included in this analysis. The high-dose atorvastatin treatment can significantly reduce the incidence of CIN (OR 0.46, 95% CI 0.35-0.62, p<0.00001). The benefit was consistent in comparison with the low-dose group (OR 0.41, 95% CI 0.25-0.66, p=0.0003) and the placebo group (OR 0.50, 95% CI 0.26-0.98, p=0.04). Our study demonstrates that high-dose statin pretreatment shows a benefit specifically in reducing the incidence of contrast-induced acute kidney injury in patients undergoing CAG, especially compared with low-dose statin pretreatment.

Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19.

Naturally secreted nanovesicles, known as exosomes, play important roles in stem cell-mediated cardioprotection. We have previously demonstrated that atorvastatin (ATV) pretreatment improved the cardioprotective effects of mesenchymal stem cells (MSCs) in a rat model of acute myocardial infarction (AMI). The aim of this study was to investigate if exosomes derived from ATV-pretreated MSCs exhibit more potent cardioprotective function in a rat model of AMI and if so to explore the underlying mechanisms. Exosomes were isolated from control MSCs (MSC-Exo) and ATV-pretreated MSCs (MSCATV-Exo) and were then delivered to endothelial cells and cardiomyocytes in vitro under hypoxia and serum deprivation (H/SD) condition or in vivo in an acutely infarcted Sprague-Dawley rat heart. Regulatory genes and pathways activated by ATV pretreatment were explored using genomics approaches and functional studies. In vitro, MSCATV-Exo accelerated migration, tube-like structure formation, and increased survival of endothelial cells but not cardiomyocytes, whereas the exosomes derived from MSCATV-Exo-treated endothelial cells prevented cardiomyocytes from H/SD-induced apoptosis. In a rat AMI model, MSCATV-Exo resulted in improved recovery in cardiac function, further reduction in infarct size and reduced cardiomyocyte apoptosis compared to MSC-Exo. In addition, MSCATV-Exo promoted angiogenesis and inhibited the elevation of IL-6 and TNF-α in the peri-infarct region. Mechanistically, we identified lncRNA H19 as a mediator of the role of MSCATV-Exo in regulating expression of miR-675 and activation of proangiogenic factor VEGF and intercellular adhesion molecule-1. Consistently, the cardioprotective effects of MSCATV-Exo was abrogated when lncRNA H19 was depleted in the ATV-pretreated MSCs and was mimicked by overexpression of lncRNA H19. Exosomes obtained from ATV-pretreated MSCs have significantly enhanced therapeutic efficacy for treatment of AMI possibly through promoting endothelial cell function. LncRNA H19 mediates, at least partially, the cardioprotective roles of MSCATV-Exo in promoting angiogenesis.

Effect of loading dose of atorvastatin therapy prior to percutaneous coronary intervention in patients with acute coronary syndrome: a meta-analysis of six randomized controlled trials.

PurposeThe study sought to summarize the evidence of pre-procedural atorvastatin therapy to improve the prognosis of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI).Patients and methodsWe searched PubMed and Embase from inception to July 2018 for randomized controlled trials that compared loading dose atorvastatin pretreatment with no or low dose for the prevention of cardiovascular events. The primary end points were all-cause mortality and myocardial infarction (MI) at 30 days. The secondary end point was 30-day major adverse cardiovascular events (MACE), a composite of all-cause mortality, MI, and revascularization.ResultsSix trials with 4,991 individuals were included in our meta-analysis. High-dose atorvastatin preloading before PCI was associated with a 27% relative reduction in MI (OR: 0.73, 95% CI, 0.56–0.94, P=0.015). All-cause mortality was nonsignificantly reduced by early treatment with high-potency atorvastatin (OR: 0.94, 95% CI, 0.69–1.30, P=0.725). There was a 20% reduction in MACE in the group of patients treated with statin loading prior to PCI (OR: 0.80, 95% CI, 0.66–0.97, P=0.026). When stratified according to the diagnosis of ACS, the results of MACE were only significant for those ST-elevation myocardial infarction patients undergoing PCI (OR: 0.67, 95% CI, 0.48–0.94, P=0.022) and were not noted in the group of non-ST elevation ACS patients (OR: 0.65, 95% CI, 0.35–1.22, P=0.179).ConclusionHigh-dose atorvastatin pretreatment leads to a significant reduction in MI and MACE at 30 days in ACS patients undergoing PCI, especially in ST-segment elevation MI.

Efficacy Evaluation of High-Dose Atorvastatin Pretreatment in Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

BackgroundIt is unclear whether high-dose atorvastatin pretreatment benefits acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). To clarify this issue, we performed a meta-analysis of the published literature.Material/MethodsRandomized controlled trials (RCTs) assessing high-dose atorvastatin pretreatment in ACS patients undergoing PCI were enrolled. Short-term major adverse cardiac events (MACEs), changes in serum high-sensitivity C-reactive protein (hs-CRP), peak creatine kinase-myocardial band (CK-MB) level, and thrombolysis in myocardial infarction (TIMI) grade 3 flow after PCI were studied as clinical outcomes.ResultsSeventeen RCTs including 10 072 patients were retrieved. High-dose atorvastatin showed greater benefits in reducing the incidence of short-term MACEs (OR 0.72; 95% CI: 0.56 to 0.94; P=0.01) and hs-CRP level (SMD −1.59; 95% CI: −2.38 to −0.80; P<0.0001) among ACS patients after PCI. No significant difference was found between the 2 groups in terms of peak CK-MB (SMD −0.34; 95% CI: −0.79 to 0.10; P=0.13) or final TIMI flow grade 3 (OR 1.31; 95% CI: 0.73 to 2.36; P=0.36) after PCI. High-dose atorvastatin therapy also was not associated with alanine aminotransferase (ALT) elevation (OR 1.95; 95% CI: 0.95 to 4.03; P=0.07).ConclusionsThe results of this meta-analysis suggest that high-dose atorvastatin pretreatment reduces the incidence of short-term MACEs and hs-CRP level without increasing drug-induced hepatotoxicity in ACS patients after PCI.

A15599 Atorvastatin pretreatment improves migration ability of mesenchymal stem cells via the miR-146a/ CXCR4 pathway

A15599 Atorvastatin pretreatment improves migration ability of mesenchymal stem cells via the miR-146a/ CXCR4 pathway

Atorvastatin Pretreatment Attenuates Ischemic Brain Edema by Suppressing Aquaporin 4

Background: Cerebral edema, a serious complication of acute cerebral infarction, has a crucial impact on morbidity and mortality in the early stage of cerebral infarction. And aquaporin 4 (AQP4), a bidirectional water transporting protein, plays a pivotal role in edema formation. At experimental model, it has proven that atorvastatin could exert pleiotropic neuroprotection on acute cerebral infarction independent of its cholesterol-lowering action. It was a common protective manifestation that atorvastatin can reduce the infarct volume and cerebral edema. However, little is known about atorvastatin improving ischemic brain edema by regulating AQP4 expression. This study intended to investigate the neuroprotection effects of atorvastatin pretreatment in rats with cerebral ischemia and further explore the potential relationship between atorvastatin and AQP4 expression. Methods: Fifty-one adult male Sprague Dawley rats were randomly divided into 3 groups: sham, middle cerebral artery occlusion (MCAO), and atorvastatin pretreatment (Ator) group. For Ator group, 20 mg/kg of atorvastatin injectable suspension was administered once for 7days by gavage before operation, whereas the others were administered the same volume of saline matching. Except for sham group, MCAO and Ator groups were subjected to permanent MCAO by modified intraluminal suture method. Infarct volume, neurological deficit, brain water content (BWC), immunohistochemistry, western blot, and polymerase chain reaction (PCR) were measured at 24 hours after MCAO. Results: Compared with sham group, the mNSS, infarct volume, and BWC of ischemic hemisphere were significantly increased (P < 0.001) in MCAO group. Positive cells and protein levels of p-p38MAPK and AQP4 in peri-infarction were significantly increased (P < 0.01). The mRNA levels of p38MAPK and AQP4 were also prominently upregulated (P < 0.01). Interestingly, preadministration of atorvastatin dramatically decreased infarct volume and the BWC of ischemic hemisphere compared with MCAO group (P < 0.05). The overexpressions of p-p38MAPK and AQP4 in peri-infarction were significantly decreased (P < 0.05) and their mRNA levels were downregulated by atorvastatin pretreatment (P < 0.05). Neurological deficits were also dramatically improved (P < 0.001). Conclusion: To the best of our knowledge, this is the first study that demonstrates an effect of atorvastatin on expression of AQP4, and we propose that decreased AQP4 expression through a p38MAPK-suppression pathway may be the mechanism of atorvastatin alleviating ischemic cerebral edema.

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.

Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.