Pravastatin Treatment Research Articles

The effect of hydrophilic statins on adiponectin, leptin, visfatin, and vaspin levels in streptozocin-induced diabetic rats.

Statins may affect glucose metabolism through adipokines. The aim of this study was to measure the effects of hydrophilic statins on the levels of several adipokines in diabetic rats. Wistar albino rats were divided into four groups: healthy control, untreated diabetic, diabetic treated with pravastatin, and diabetic treated with rosuvastatin. Diabetes was induced by intraperitoneal injection of STZ. Thereafter, 20 mg/kg/day doses of either pravastatin or rosuvastatin were administered to the treated diabetic rats for 8 weeks. At the end of the experiment, the body weights, fasting blood glucose levels, serum insulin levels, and insulin resistance, as well as the serum adiponectin, leptin, visfatin, and vaspin levels, were measured. Fasting blood glucose and insulin resistance levels were significantly higher, whereas insulin levels and body weight were significantly lower in the untreated diabetic group than in the control group. Diabetes caused significant decreases in adiponectin, leptin, and vaspin levels but a significant increase in visfatin levels. Pravastatin treatment significantly increased body weight and decreased fasting blood glucose levels, whereas rosuvastatin decreased body weight but did not affect fasting blood glucose levels. Pravastatin caused significant increases in both adiponectin and vaspin levels. However, rosuvastatin did not affect the adiponectin level but caused a significant decrease in the vaspin levels. Both pravastatin and rosuvastatin treatments decreased the leptin and visfatin levels. In conclusion, pravastatin is more effective at improving fasting blood glucose levels and body weight in diabetic rats, probably by increasing adiponectin and vaspin levels.

Effect of bisphosphonates and statins on the in vitro radiosensitivity of breast cancer cell lines.

Early-stage breast cancer is usually treated with breast-conserving surgery followed by adjuvant radiation therapy. Acute skin toxicity is a common radiation-induced side effect experienced by many patients. Recently, a combination of bisphosphonates (zoledronic acid) and statins (pravastatin), or ZOPRA, was shown to radio-protect normal tissues by enhancing DNA double-strand breaks (DSB) repair mechanism. However, there are no studies assessing the effect of ZOPRA on cancerous cells. The purpose of this study is to characterize the in vitro effect of the zoledronic acid (ZO), pravastatin (PRA), and ZOPRA treatment on the molecular and cellular radiosensitivity of breast cancer cell lines. Two breast cancer cell lines, MDA MB 231 and MCF-7, were tested. Cells were treated with different concentrations of pravastatin (PRA), zoledronate (ZO), as well as their ZOPRA combination, before irradiation. Anti-γH2AX and anti-pATM immunofluorescence were performed to study DNA DSB repair kinetics. MTT assay was performed to assess cell proliferation and viability, and flow cytometry was performed to analyze the effect of the drugs on the cell cycle distribution. The clonogenic assay was used to assess cell survival. ZO, PRA, and ZOPRA treatments were shown to increase the residual number of γH2AX foci for both cell lines. ZOPRA treatment was also shown to reduce the activity of the ATM kinase in MCF-7. ZOPRA induced a significant decrease in cell survival for both cell lines. Our findings show that pretreatment with ZOPRA can decrease the radioresistance of breast cancer cells at the molecular and cellular levels. The fact that ZOPRA was previously shown to radioprotect normal tissues, makes it a good candidate to become a therapeutic window-widening drug.

The Effects of Prenatal Pravastatin Treatment in the Rabbit Fetal Growth Restriction Model.

Fetal growth restriction (FGR) remains without an effective prenatal treatment. Evidence from murine FGR models suggests a beneficial effect of prenatal pravastatin. Since the rabbit hemodichorial placenta more closely resembles the human condition, we investigated the effects of prenatal maternal pravastatin administration in the rabbit FGR model. At a gestational age of 25 days (term 31d), pregnant dams underwent partial uteroplacental vessel ligation (UPVL) in one uterine horn to induce FGR, leaving the other horn as a control. Dams were randomized to either receive 5 mg/kg/d pravastatin dissolved in their drinking water or normal drinking water until delivery. At GA 30d, the rabbits were delivered and were divided into four groups: control without pravastatin (C/NoPrav), FGR without pravastatin (FGR/NoPrav), FGR with pravastatin (FGR/Prav), and controls with pravastatin (C/Prav). The newborn rabbits underwent pulmonary functional assessment and neurobehavioral assessment, and they were harvested for alveolar morphometry or neuropathology. The placentas underwent histology examination and RNA expression. Birth weight was lower in the FGR groups (FGR/Prav, FGR/NoPrav), but there was no difference between FGR/Prav and C/NoPrav. No differences were noted in placental zone proportions, but eNOS in FGR/Prav placentas and VEGFR-2 in FGR/Prav and C/Prav were upregulated. There were no differences in pulmonary function assessment and alveolar morphometry. FGR/Prav kittens had increased neurosensory scores, but there were no differences in neuromotor tests, neuron density, apoptosis, and astrogliosis. In conclusion, in the rabbit FGR model, pravastatin upregulated the expression of VEGFR-2 and eNOS in FGR placentas and was associated with higher neurosensory scores, without measurable effects on birthweight, pulmonary function and morphology, and neuron density.

Correlation analysis of cancer incidence after pravastatin treatment

Background: Few studies have investigated the cancer-preventive effects of statins, which are known to protect against cardio-cerebrovascular diseases. In this study, we analyzed the degree to which pravastatin, a low-potency statin, could prevent cancer.Methods: This retrospective cohort study used data from the Korean National Health Insurance Service database. Patients diagnosed with diabetes after the age of 50 years were divided into a pravastatin group and a control group that did not receive any statin prescriptions.Results: This study included 557 patients in the pravastatin group and 2,221 patients in the control (no statin) group. During the 5-year follow-up, the incidence of cancer was 16.7% (93 of 557 patients) in the pravastatin group and 19.9% (442 of 2,221 patients) in the control group. The incidence of cancer was 22% higher in the control group than in the pravastatin group (hazard ratio, 1.22; 95% confidence interval, 0.97–1.52; P=0.09). Death from various causes occurred at a 45% higher frequency in the control group than in the pravastatin group (hazard ratio, 1.45; 95% confidence interval, 0.99–2.12; P=0.06). However, neither of those relationships reached statistical significance.Conclusions: Although pravastatin use did not show a significant causal relationship with cancer incidence, fewer cases of cancer occurred in pravastatin users than in controls. However, further large-scale studies are required to confirm these findings.

Long-term neurodevelopmental follow-up of children exposed to pravastatin in utero

Preeclampsia, especially before term, increases the risk of child neurodevelopmental adverse outcomes. Biological plausibility, preclinical studies, and pilot clinical trials conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Obstetric-Fetal Pharmacology Research Centers Network support the safety and use of pravastatin to prevent preeclampsia. This study aimed to determine the effect of antenatal pravastatin treatment in high-risk pregnant individuals on their child's health, growth, and neurodevelopment. This was an ancillary follow-up cohort study of children born to mothers who participated in the Obstetric-Fetal Pharmacology Research Centers Network pilot trials of pravastatin vs placebo in individuals at high risk of preeclampsia (ClinicalTrials.gov; identifier NCT01717586). After obtaining written informed consent (and assent as appropriate), the parent was instructed to complete the Child Behavior Checklist. To assess the child's motor, cognitive, and developmental outcomes, a certified and blinded study psychologist completed child motor, cognitive, emotional, and behavioral assessments using validated tools. Given the small number of individuals in the studies, the 10- and 20-mg pravastatin groups were combined into 1 group, and the results of the pravastatin group were compared with that of the placebo group. Of 40 children born to mothers in the original trial, 30 (15 exposed in utero to pravastatin and 15 to placebo) were enrolled in this follow-up study. The time of follow-up, which was 4.7 years (interquartile range, 2.5-6.9), was not different between children in the pravastatin group and children in the placebo group. There was no difference in the child's body mass index percentiles per sex and corrected age, the rates of extremes of body mass index percentiles, or the report of any other medical or developmental complications between the 2 groups. No child born in the pravastatin group had any limitation in motor assessment compared with 2 children (13.3%) who walked with difficulty and 4 children (26.7%) who had reduced manual abilities in the placebo group. Moreover, children born to mothers who received pravastatin had a higher general mean conceptual ability score (98.2±16.7 vs 89.7±11.0; P=.13) and a lower frequency (15.4% vs 35.7%; P=.38) of having a score of <85 (ie, 1 standard deviation lower than the mean) compared with those in the placebo group. Finally, there was no difference in the parents' report on the Child Behavior Checklist between the 2 groups. This study reported on the long-term neuromotor, cognitive, and behavioral outcomes among children exposed to pravastatin in utero during the second and third trimesters of pregnancy. Although the data were limited by the original trial's sample size, no identifiable long-term neurodevelopmental safety signal was evident with the use of pravastatin during pregnancy. This favorable neonatal risk-benefit analysis justifies continued research using pravastatin in clinical trials.

Abstract 15254: Acta2 Missense Variant Increases Atherosclerotic Plaque Burdern by Heat Shock Factor 1-Driven Augmented Phenotypic Modulation of Smooth Muscle Cells

ACTA2 encodes the contractile protein smooth muscle α-actin expressed in smooth muscle cells (SMCs). A heterozygous pathogenic variant in ACTA2 , p.R149C, predisposes to premature coronary artery disease (CAD) in the absence of risk factors. Recent studies have determined that SMCs contribute to atherosclerotic plaque formation after undergoing phenotypic modulation, characterized by de-differentiation and increased expression of macrophage, fibroblast, stem, and osteogenic markers. This SMC modulation is driven in part by exogenous cholesterol entering the endoplasmic reticulum (ER) and activating ER stress, specifically PERK signaling. To determine how a mutation in SM α-actin predisposes to atherosclerosis, Acta2 R149C/+ mice were crossed into Apoe -/- mice and fed a high fat diet for 3 months. Despite no differences in serum lipid levels, the Acta2 R149C/+ Apoe -/- mice have a 3-fold increased plaque burden compared to Apoe -/- mice. SMCs explanted from Acta2 R149C/+ mice have phenotypic modulation at baseline while WT SMCs do not. We determined that misfolding of the R149C SMα-actin activates heat shock factor 1 (HSF1), which increases endogenous cholesterol biosynthesis through increasing HMG-CoA reductase expression. The increase in endogenous cholesterol levels induces ER stress, activates PERK, and augments both modulation of SMCs and atherosclerotic plaque formation. ScRNA sequencing confirms increased HSF1 and PERK signaling and modulation in SMCs in the mutant mice. Importantly, pravastatin treatment dramatically lowers plaque burden to similar low levels of plaque burden in both the Acta2 R149C/+ Apoe -/- and Apoe -/- mice (Fig. 1a) . These studies identify a novel mechanism by which mutant SM α-actin increases endogenous cholesterol biosynthesis and drives atherosclerotic plaque formation, a mechanism that also informs as to why statins are effective in individuals at risk for CAD who do not have elevated plasma cholesterol levels (Fig. 1b) .

Abstract P100: Combination Treatment Of Resveratrol And Pravastatin Decreases NF-κB Expression In HUVEC Model Of Preeclampsia

Introduction: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by new-onset hypertension with new-onset proteinuria or other signs/symptoms of preeclampsia after 20 weeks’ gestation. It is associated with an increase in anti-angiogenic, oxidative, and pro-inflammatory factors including soluble fms-like tyrosine kinase-1 (sFLT-1). While a previous study established cumulative beneficial effects of resveratrol and pravastatin on cardiovascular disease, no study has been conducted regarding this combination therapy on PE. Hypothesis: The combination of resveratrol and pravastatin is more effective in reversing endothelial damage than the individual drugs alone. Methods: Human umbilical vein endothelial cells (HUVECs) were incubated with sFLT-1 (25ng/ml) for 24 hours. HUVECs were then treated with either 20μM resveratrol, 20μM pravastatin, 20μM resveratrol + 20μM pravastatin, or left untreated. Cells were lysed and western blotting was performed using primary antibodies against: eNOS, phospho-eNOS and NF-κB. Immunoreactive bands were visualized and quantified using Image Studio Lite Ver 5.2. Results: Pre-treatment with sFLT-1 increased expression of NF-κB compared to untreated controls (Mean±SEM: 53.57±24.98 vs 27.78±15.85 p=0.0346), while combination treatment of sFLT-1 pre-treated cells reduced expression of NF-κB (Mean: 53.57±24.98 vs 38.99±26.81 p=0.0186). eNOS expression was not changed by pre-treatment with sFLT-1, but expression was improved by pravastatin only in control cells (Mean: 3.084±0.6266 vs 4.737±1.247 p=0.0463). Phospho-eNOS expression was improved by pravastatin treatment in both control cells (Mean: 1.309±0.4633 vs 2.467±0.8298 p=0.0213) and in sFLT-1 pre-treated cells (Mean 1.235±0.3765 vs 2.716±0.9470 p=0.0347). Finally, phospho-eNOS expression was improved by combination treatment in control cells (Mean: 1.309±0.4633 vs 1.825±0.5793 p=0.0136). Conclusions: Our results show that treatment with resveratrol and pravastatin was more effective at decreasing inflammation than individual treatments, therefore suggesting that the combination therapy could be a helpful treatment for PE pathophysiology.

Microarchitectural Changes of Cardiovascular Calcification in Response to In Vivo Interventions Using Deep-Learning Segmentation and Computed Tomography Radiomics.

Coronary calcification associates closely with cardiovascular risk, but its progress is accelerated in response to some interventions widely used to reduce risk. This paradox suggests that qualitative, not just quantitative, changes in calcification may affect plaque stability. To determine if the microarchitecture of calcification varies with aging, Western diet, statin therapy, and high intensity, progressive exercise, we assessed changes in a priori selected computed tomography radiomic features (intensity, size, shape, and texture). Longitudinal computed tomography scans of mice (Apoe-/-) exposed to each of these conditions were autosegmented by deep learning segmentation, and radiomic features of the largest deposits were analyzed. Over 20 weeks of aging, intensity and most size parameters increased, but surface-area-to-volume ratio (a measure of porosity) decreased, suggesting stabilization. However, texture features (coarseness, cluster tendency, and nonuniformity) increased, suggesting heterogeneity and likely destabilization. Shape parameters showed no significant changes, except sphericity, which showed a decrease. The Western diet had significant effects on radiomic features related to size and texture, but not intensity or shape. In mice undergoing either pravastatin treatment or exercise, the selected radiomic features of their computed tomography scans were not significantly different from those of their respective controls. Interestingly, the total number of calcific deposits increased significantly less in the 2 intervention groups compared with the respective controls, suggesting more coalescence and/or fewer de novo deposits. Thus, aging and standard interventions alter the microarchitectural features of vascular calcium deposits in ways that may alter plaque biomechanical stability.

Selective Growth Suppressive Effect of Pravastatin on Senescent Human Lung Fibroblasts.

Various chemical reagents containing inhibitors of mitochondrial activity, antioxidants, nuclear factor-kappa B (NF-kB) inhibitor, mammalian target of rapamycin (mTOR) inhibitor and other clinical therapeutics were screened in order to identify those that selectively decrease the viability of senescent human lung fibroblasts. Cell viability was measured using the CCK-8 assay. The results showed that pravastatin, a drug for hyperlipidemia, decreased the viability of senescent cells but not non-senescent cells. The effect of pravastatin on senescent cells is thought to be due to the inhibition of cell proliferation, rather than cell death. The effect of pravastatin was further investigated using the glucose metabolism assay, which showed that glucose consumption was inhibited both in non-senescent and senescent cells and intracellular nicotinamide adenine dinucleotide (NAD) was decreased in senescent cells. Changes to the mRNA expression levels of senescence-associated genes in response to pravastatin treatment were quantified by real-time-qPCR. There were no significant changes in the relative mRNA expression levels of IL-1β, p16, p21, and p53 in pravastatin-treated non-senescent cells, whereas the expression of IL-1β and p16 were increased by pravastatin only in senescent cells. The results of this study suggest that pravastatin does not induce senolysis, but rather selectively inhibits the proliferation of senescent cells and that cellular senescence is enhanced by decreasing intracellular NAD and promoting IL-1β production.

In Vivo Pravastatin Treatment Reverses Hypercholesterolemia Induced Mitochondria-Associated Membranes Contact Sites, Foam Cell Formation, and Phagocytosis in Macrophages.

Statins are successful drugs used to treat hypercholesterolemia, a primary cause of atherosclerosis. In this work, we investigated how hypercholesterolemia and pravastatin treatment impact macrophage and mitochondria functions, the key cell involved in atherogenesis. By comparing bone marrow-derived macrophages (BMDM) of wild-type (WT) and LDL receptor knockout (LDLr−/−) mice, we observed hypercholesterolemia increased the number of contact sites at mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), enhanced mitochondrial hydrogen peroxide release, altered the gene expression of inflammatory markers, and increased oxidized LDL (ox-LDL) uptake and phagocytic activity. Three months of in vivo pravastatin treatment of LDLr−/− mice reversed the number of contact sites at the MAM, ox-LDL uptake, and phagocytosis in LDLr−/− BMDM. Additionally, pravastatin increased BMDM mitochondrial network branching. In peritoneal macrophages (PMs), hypercholesterolemia did not change MAM stability, but stimulated hydrogen peroxide production and modulated gene expression of pro- and anti-inflammatory markers. It also increased mitochondrial branching degree and had no effects on ox-LDL uptake and phagocytosis in PM. Pravastatin treatment increased superoxide anion production and changed inflammation-related gene expression in LDLr−/− PM. In addition, pravastatin increased markedly the expression of the mitochondrial dynamics-related genes Mfn2 and Fis1 in both macrophages. In summary, our results show that hypercholesterolemia and pravastatin treatment affect macrophage mitochondria network structure as well as their interaction with the endoplasmic reticulum (ER). These effects impact on macrophage conversion rates to foam cell and macrophage phagocytic capacity. These findings associate MAM stability changes with known mechanisms involved in atherosclerosis progression and resolution.

Vitamin D Deficiency Impacts Exposure and Response of Pravastatin in Male Rats by Altering Hepatic OATPs

This study aimed to determine the effect of vitamin D (VD) deficiency on the efficacy and pharmacokinetics of pravastatin and clarify whether the effects are mediated by Organic anion-transporting polypeptides (OATPs). Experiments were conducted in rats to explore the effect of VD deficiency on the pharmacodynamics and pharmacokinetics of pravastatin. In the pharmacodynamic study, rats were fed a VD-free or VD-supplement high-fat diet for 25–30 days, and plasma 25(OH)VD was dynamically monitored. The response of pravastatin (changes in blood lipids) on rats were then examined after 15 days of pravastatin treatment. In the pharmacokinetic study, rats were fed a VD-free or VD-supplement diet for 25–30 days. The pharmacokinetics of single oral dose pravastatin was then studied, and intestinal and hepatic Oatp1a1 and Oatp2b1 expression was determined using quantitative polymerase chain reaction (qPCR) and western blot. Furthermore, OATP1B1 and OATP2B1 expression in Huh7 cells with or without 1.25(OH)2D were assessed via qPCR and western blot. For the pharmacodynamic study, the decrease of total cholesterol and increase of high-density lipoprotein cholesterol in VD-deficient rats were smaller than in VD-sufficient rats, indicating that VD deficiency reduced the response of pravastatin in rats. For the pharmacokinetic study, the plasma exposure slightly increased, and liver exposure decreased in VD-deficient rats, but not significantly. VD deficiency decreased the Oatp1a1 and Oatp2b1 expression in the liver, but not in the small intestine. Similarly, OATP1B1 and OATP2B1 protein levels in Huh7 cells were reduced when 1.25(OH)2D was absent. In conclusion, VD deficiency can decrease the response of pravastatin in rats by reducing the liver pravastatin exposure and expression of hepatic OATPs, consistent with the extended hepatic clearance model theory.

Pravastatin effect on Obstetrics Complications Associated with Uteroplacental Insufficiency: A systematic review and Meta-Analysis

To assess statins' effect on pregnancy prolongation as well as neonatal and maternal morbidity in a distinct group of uteroplacental insufficiency disorders. Electronic databases were searched from 1953 to April 2021 for cohort studies and randomized controlled trials evaluating the effect of statins treatment on pregnancies with uteroplacental insufficiency disorders compares to control. The primary outcome was pregnancy prolongation from randomization. Secondary outcomes included neonatal parameters such as birth weight, death, and critical care unit admission, and maternal outcome occurrence as the development of preeclampsia. Pooled odds ratios were calculated using a random-effects model and meta-regression was utilized when applicable. Seven cohort and RCTs studies were included in the analysis with a total of 200 parturients with uteroplacental insufficiency disorders. Of whom, 105 were treated with pravastatin and 95 did not. Parturients that received Pravastatin showed significant prolongation of gestational age from randomization to delivery, (mean difference= 6.1 weeks, 95%CI;1.4-10.8, p=0.01, I2=98%) and less neonatal critical care unit admission (OR=0.21, 95%CI; 0.07-0.64, p=0.01, I2=32%). There was a trend in a decrease in perinatal death (OR=0.3, 95%CI;0.08-1.02, p=0.05, I2=19%), and an increase in neonatal birth weight (mean difference=771gr, CI; 2–1540, p=0.05, I2=97.4%). A new diagnosis of preeclampsia occurred less under Pravastatin treatment, yet not statistically significant (OR 0.38, CI;0.13–1.12, p=0.08, I=0%). In a meta-regression, an association between prolongation of pregnancy from randomization (R2=0.7) and birth weight (R2=0.6) to study type (RCT vs cohort) was demonstrated. No statistically significant dose-response effect or gestational age at initiation of treatment effect was found. Treatment with Pravastatin in parturients who have a high risk for developing uteroplacental insufficiency-associated disorders or have an existing preeclampsia/severe IUGR may improve their neonatal outcomes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy.

BackgroundRadiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy.MethodsThe radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression.FindingUsing a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy.InterpretationPS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage.FundingAs stated in the Acknowledgments

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Effect of folic acid combined with pravastatin on arteriosclerosis in elderly hypertensive patients with lacunar infarction.

This study aimed to assess the effect of folic acid combined with pravastatin on atherosclerosis-related indexes in elderly patients with hypertension complicated with lacunar cerebral infarction.A total of 134 elderly hypertensive patients with lacunar cerebral infarction were randomly divided into 3 groups using the random number table method. Group A, the folic acid group, had 45 cases and received low-dose folic acid (0.8 mg/d) treatment on the basis of antihypertensive treatment. Group B, the pravastatin group, had 45 cases and received pravastatin (20 mg/d) treatment on the basis of antihypertensive treatment. Group C, the folic acid combined with the pravastatin group, had 44 cases. Members of this group received pravastatin (20 mg/d) and low-dose folic acid (0.8 mg/d) based on antihypertensive treatment. Levels of folic acid, homocysteine (Hcy), tumor necrosis factor alpha (TNF-a), matrix metallopeptidase 9 (MMP-9), cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were measured by ELISA before treatment in all 3 groups. Carotid intima-media thickness (IMT) was measured using ultrasound, and systolic and diastolic blood pressure were measured with a mercury column. After 8 weeks of treatment, the levels of folic acid, Hcy, TNF-a, MMP-9, TC, LDL-C, and systolic and diastolic blood pressure were compared among the 3 groups. IMT levels were measured at 12 weeks of treatment.After 8 weeks of treatment, compared with group B, patients in groups A and C had folic acid levels significantly higher than baseline levels, with significantly lower Hcy levels (both P < .05). Patients in group C presented significantly decreased TNF-a, MMP-9, TC, and LDL-C levels and systolic and diastolic blood pressure after 8 weeks of treatment, compared with those in groups A and B (both P < .05). These patients also showed significantly decreased IMT levels compared with those in the other groups (P < .05).Low-dose folic acid combined with pravastatin in elderly patients with lacunar cerebral infarction can reduce the level of homocysteine, improve the degree of carotid atherosclerosis, protect vascular endothelium, and reduce blood lipids and blood pressure, presenting better benefits than pravastatin alone.

Effect of pravastatin on erythrocyte membrane fatty acid contents in patients with chronic kidney disease.

BackgroundStatin treatment has decreased the risk of cardiovascular events in patients with chronic kidney disease (CKD). Erythrocyte membrane oleic acid level is higher in patients with acute coronary syndrome. This study aimed to evaluate the effect of pravastatin on the erythrocyte membrane fatty acid (FA) contents in patients with CKD.MethodsSixty-two patients were enrolled from January 2017 to March 2019 (NCT02992548). Pravastatin was initially administered at a dose of 20 mg for 24 weeks. The pravastatin dose was increased to 40 mg after 12 weeks if it was necessary to control dyslipidemia. The primary outcome was change in erythrocyte membrane FA, including oleic acid, after pravastatin treatment for 24 weeks.ResultsForty-five patients finished this study, and there was no adverse effect related to pravastatin. Compared with baseline, total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased after pravastatin treatment. Compared with baseline, saturated FA, oleic acid, and arachidonic acid levels were significantly increased and polyunsaturated FA and linoleic acid (LA) levels were significantly decreased after pravastatin treatment. There was also a decrease in eicosapentaenoic acid after pravastatin treatment in CKD patients with estimated glomerular filtration rate < 60 mL/min/1.73 m2.ConclusionAdministration of pravastatin in patients with CKD leads to a decrease in FA known to be protective against the risk of CVD. Omega-3 FA or LA supplementation might be necessary to recover changes in erythrocyte membrane FA contents when pravastatin is used for treating dyslipidemia in patients with CKD.

Statin Effects on Vascular Calcification: Microarchitectural Changes in Aortic Calcium Deposits in Aged Hyperlipidemic Mice.

[Figure: see text].

Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. Although children with ADPKD show normal renal function, cyst development is already occurring. In this study, we aimed to identify markers and associated molecular pathways of disease progression in children and young adults with ADPKD. Plasma samples were collected during a 3-year randomized, double-blind, placebo-controlled, phase III clinical trial that was designed to test the efficacy of pravastatin on slowing down ADPKD progression in pediatric patients. Samples from 58 patients were available at baseline and at the 3-year endpoint of the study, respectively. Furthermore, plasma samples from 98 healthy children were used as controls. Metabolomic analysis was performed using liquid chromatography-tandem mass spectrometry and differences in metabolic profiles over time and within study groups were evaluated. While pravastatin therapy led to a decrease in a percent change of total kidney volume (HtTKV) in ADPKD patients, it had minimal effects on metabolite changes. Oxidative stress, endothelial dysfunction, inflammation and immune response were the most affected signaling pathways that distinguished healthy from diseased children. Pathway analysis revealed that metabolites in the arginine metabolism (urea and nitric oxide cycles), asparagine and glutamine metabolism, in the methylation cycle and kynurenine pathway were significantly changed between healthy and children with ADPDK and continued to diverge from the control levels while the disease progressed. Detected metabolite changes were primarily governed by disease progression, and less by pravastatin treatment. Identified metabolic pathways, from arginine and asparagine to kynurenine metabolism could present therapeutic targets and should be further investigated for potential to treat ADPKD progression at an early stage.

Pravastatin Promotes Endothelial Colony-Forming Cell Function, Angiogenic Signaling and Protein Expression In Vitro.

Endothelial dysfunction is a primary feature of several cardiovascular diseases. Endothelial colony-forming cells (ECFCs) represent a highly proliferative subtype of endothelial progenitor cells (EPCs), which are involved in neovascularization and vascular repair. Statins are known to improve the outcome of cardiovascular diseases via pleiotropic effects. We hypothesized that treatment with the 3-hydroxy-3-methyl-glutaryl–coenzyme A (HMG-CoA) reductase inhibitor pravastatin increases ECFCs’ functional capacities and regulates the expression of proteins which modulate endothelial health in a favourable manner. Umbilical cord blood derived ECFCs were incubated with different concentrations of pravastatin with or without mevalonate, a key intermediate in cholesterol synthesis. Functional capacities such as migration, proliferation and tube formation were addressed in corresponding in vitro assays. mRNA and protein levels or phosphorylation of protein kinase B (AKT), endothelial nitric oxide synthase (eNOS), heme oxygenase-1 (HO-1), vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and endoglin (Eng) were analyzed by real time PCR or immunoblot, respectively. Proliferation, migration and tube formation of ECFCs were enhanced after pravastatin treatment, and AKT- and eNOS-phosphorylation were augmented. Further, expression levels of HO-1, VEGF-A and PlGF were increased, whereas expression levels of sFlt-1 and Eng were decreased. Pravastatin induced effects were reversible by the addition of mevalonate. Pravastatin induces beneficial effects on ECFC function, angiogenic signaling and protein expression. These effects may contribute to understand the pleiotropic function of statins as well as to provide a promising option to improve ECFCs’ condition in cell therapy in order to ameliorate endothelial dysfunction.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study.

This study aimed to analyze the effect of pravastatin on angiogenic factors, feto-maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (-34.8 to 197.3) in the control group but decreased by a median (interquartile range) of -10.1 (-53.1 to -0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. · Pravastatin improves sFlt-1/PlGF in FGR.. · Pregnancy duration tended to be greater in treated women.. · Birthweight tended to be greater in treated women..