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BMC Medicine Mar 2023Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC-EV) have a superior cardiac repair effect on...
Atorvastatin-pretreated mesenchymal stem cell-derived extracellular vesicles promote cardiac repair after myocardial infarction via shifting macrophage polarization by targeting microRNA-139-3p/Stat1 pathway.
BACKGROUND
Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (MSCs) pretreated with atorvastatin (ATV) (MSC-EV) have a superior cardiac repair effect on acute myocardial infarction (AMI). The mechanisms, however, have not been fully elucidated. This study aims to explore whether inflammation alleviation of infarct region via macrophage polarization plays a key role in the efficacy of MSC-EV.
METHODS
MSC-EV or MSC-EV were intramyocardially injected 30 min after coronary ligation in AMI rats. Macrophage infiltration and polarization (day 3), cardiac function (days 0, 3, 7, 28), and infarct size (day 28) were measured. EV small RNA sequencing and bioinformatics analysis were conducted for differentially expressed miRNAs between MSC-EV and MSC-EV. Macrophages were isolated from rat bone marrow for molecular mechanism analysis. miRNA mimics or inhibitors were transfected into EVs or macrophages to analyze its effects on macrophage polarization and cardiac repair in vitro and in vivo.
RESULTS
MSC-EV significantly reduced the amount of CD68 total macrophages and increased CD206 M2 macrophages of infarct zone on day 3 after AMI compared with MSC-EV group (P < 0.01-0.0001). On day 28, MSC-EV much more significantly improved the cardiac function than MSC-EV with the infarct size markedly reduced (P < 0.05-0.0001). In vitro, MSC-EV also significantly reduced the protein and mRNA expressions of M1 markers but increased those of M2 markers in lipopolysaccharide-treated macrophages (P < 0.05-0.0001). EV miR-139-3p was identified as a potential cardiac repair factor mediating macrophage polarization. Knockdown of miR-139-3p in MSC-EV significantly attenuated while overexpression of it in MSC-EV enhanced the effect on promoting M2 polarization by suppressing downstream signal transducer and activator of transcription 1 (Stat1). Furthermore, MSC-EV loaded with miR-139-3p inhibitors decreased while MSC-EV loaded with miR-139-3p mimics increased the expressions of M2 markers and cardioprotective efficacy.
CONCLUSIONS
We uncovered a novel mechanism that MSC-EV remarkably facilitate cardiac repair in AMI by promoting macrophage polarization via miR-139-3p/Stat1 pathway, which has the great potential for clinical translation.
Topics: Rats; Animals; Atorvastatin; Myocardial Infarction; Extracellular Vesicles; MicroRNAs; Mesenchymal Stem Cells; Macrophages; STAT1 Transcription Factor
PubMed: 36927608
DOI: 10.1186/s12916-023-02778-x -
International Journal of Molecular... Oct 2021Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of...
Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression.
Topics: Animals; Anticholesteremic Agents; Atorvastatin; Body Weight; Diet, High-Fat; Gene Expression Regulation; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipid Metabolism; Liver; Male; PPAR gamma; Rats, Sprague-Dawley; Signal Transduction; Rats
PubMed: 34681767
DOI: 10.3390/ijms222011107 -
The Annals of Pharmacotherapy Oct 2021
Topics: Atorvastatin; Gynecomastia; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male
PubMed: 33472378
DOI: 10.1177/1060028021988994 -
Hepatology Communications Dec 2023Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension.
METHODS
We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10-20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months.
RESULTS
Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed.
CONCLUSIONS
In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.
Topics: Humans; Anti-Inflammatory Agents; Atorvastatin; End Stage Liver Disease; Hypertension, Portal; Liver Cirrhosis; Severity of Illness Index; Double-Blind Method
PubMed: 38051553
DOI: 10.1097/HC9.0000000000000332 -
Journal of the American Heart... Sep 2023Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and... (Observational Study)
Observational Study
Intensive Statin Therapy Versus Upfront Combination Therapy of Statin and Ezetimibe in Patients With Acute Coronary Syndrome: A Propensity Score Matching Analysis Based on the PL-ACS Data.
Background We aimed to compare statin monotherapy and upfront combination therapy of statin and ezetimibe in patients with acute coronary syndromes (ACSs). Methods and Results The study included consecutive patients with ACS included in the PL-ACS (Polish Registry of Acute Coronary Syndromes), which is a national, multicenter, ongoing, prospective observational registry that is mandatory for patients with ACS hospitalized in Poland. Data were matched using the Mahalanobis distance within propensity score matching calipers. Multivariable stepwise logistic regression analysis, including all variables, was next used in propensity score matching analysis. Finally, 38 023 consecutive patients with ACS who were discharged alive were included in the analysis. After propensity score matching, 2 groups were analyzed: statin monotherapy (atorvastatin or rosuvastatin; n=768) and upfront combination therapy of statin and ezetimibe (n=768 patients). The difference in mortality between groups was significant during the follow-up and was present at 1 (5.9% versus 3.5%; =0.041), 2 (7.8% versus 4.3%; =0.019), and 3 (10.2% versus 5.5%; =0.024) years of follow-up in favor of the upfront combination therapy, as well as for the overall period. For the treatment, rosuvastatin significantly improved prognosis compared with atorvastatin (odds ratio [OR], 0.790 [95% CI, 0.732-0.853]). Upfront combination therapy was associated with a significant reduction of all-cause mortality in comparison with statin monotherapy (OR, 0.526 [95% CI, 0.378-0.733]), with absolute risk reduction of 4.7% after 3 years (number needed to treat=21). Conclusions The upfront combination lipid-lowering therapy is superior to statin monotherapy for all-cause mortality in patients with ACS. These results suggest that in high-risk patients, such an approach, rather than a stepwise therapy approach, should be recommended.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Acute Coronary Syndrome; Ezetimibe; Propensity Score
PubMed: 37671618
DOI: 10.1161/JAHA.123.030414 -
Aging Nov 2023Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation...
Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoEgroups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE mice in the ApoE+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6C CD45 cells and CD3 CD45 cells, as well as the blood Ly6C CD45 cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE mice.
Topics: Humans; Mice; Animals; Atorvastatin; Hypercholesterolemia; Monocytes; Heptanoic Acids; Pyrroles; Hyperlipidemias; Apolipoproteins E; Brain
PubMed: 38048213
DOI: 10.18632/aging.205217 -
Journal of Neuroinflammation Sep 2023Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the...
BACKGROUND
Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer's disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID.
METHODS
Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods.
RESULTS
Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task.
CONCLUSIONS
These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.
Topics: Animals; Mice; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperhomocysteinemia; Cognitive Dysfunction; Cognition; Alzheimer Disease; Dementia, Vascular; Homocysteine
PubMed: 37658433
DOI: 10.1186/s12974-023-02883-x -
Journal of Medical Virology Jul 2023Evidence of the effect of statins on patients with coronavirus disease (2019) COVID-19 is inconsistent. The aim of this study was to evaluate the association between...
Evidence of the effect of statins on patients with coronavirus disease (2019) COVID-19 is inconsistent. The aim of this study was to evaluate the association between chronic use of statins-both overall and by active ingredient-and severe outcomes of COVID-19 (risk of hospitalization and mortality), progression to severe outcomes, and susceptibility to the virus. We conducted a population-based case-control study with data from electronic records to assess the risk of (1) hospitalization: cases were patients admitted due to COVID-19 and controls were subjects without COVID-19; (2) mortality: cases were hospitalized patients who died due to COVID-19 and controls were subjects without COVID-19; (3) progression: cases were hospitalized COVID-19 subjects and controls were nonhospitalized COVID-19 patients; and (4) susceptibility: cases were patients with COVID-19 (both hospitalized and nonhospitalized) and controls were subjects without COVID-19. We collected data on 2821 hospitalized cases, 26 996 nonhospitalized cases, and 52 318 controls. Chronic use of atorvastatin was associated with a decreased risk of hospitalization (adjusted odds ratios [aOR] = 0.83; 95% confidence interval [CI]: 0.74-0.92) and mortality (aOR = 0.70; 95% CI: 0.53-0.93), attributable in part to a lower risk of susceptibility to the virus (aOR = 0.91; 95% CI: 0.86-0.96). Simvastatin was associated with a reduced risk of mortality (aOR = 0.59; 95% CI: 0.40-0.87). The wide degree of heterogeneity observed in the estimated odds ratios (ORs) of the different statins suggests that there is no class effect. The results of this real-world study suggest that chronic use of atorvastatin (and to a lesser degree, of simvastatin) is associated with a decrease in risk of severe COVID-19 outcomes.
Topics: Humans; COVID-19; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Case-Control Studies; Outpatients; Hospitalization; Simvastatin
PubMed: 37486310
DOI: 10.1002/jmv.28971 -
International Journal of Molecular... Oct 2021Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is...
Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol content and the organization of actin. This work analyzes the effects of the latter on the efficacy of electroporation of cancer cells. In addition, herein, electroporation was combined with calcium chloride (CaEP) to assess as well the effects of the statin on the efficacy of electrochemotherapy. Cholesterol-rich cell lines MDA-MB231, DU 145, and A375 underwent (1) 48 h preincubation or (2) direct treatment with 50 nM atorvastatin. We studied the impact of the statin on cholesterol and actin fiber organization and analyzed the cells' membrane permeability. The viability of cells subjected to PEF (pulsed electric field) treatments and CaEP with 5 mM CaCl was examined. Finally, to assess the safety of the therapy, we analyzed the N-and E-cadherin localization using confocal laser microscopy. The results of our investigation revealed that depending on the cell line, atorvastatin preincubation decreases the total cholesterol in the steroidogenic cells and induces reorganization of actin nearby the cell membrane. Under low voltage PEFs, actin reorganization is responsible for the increase in the electroporation threshold. However, when subject to high voltage PEF, the lipid composition of the cell membrane becomes the regulatory factor. Namely, preincubation with atorvastatin reduces the cytotoxic effect of low voltage pulses and enhances the cytotoxicity and cellular changes induced by high voltage pulses. The study confirms that the surface tension regulates of membrane permeability under low voltage PEF treatment. Accordingly, to reduce the unfavorable effects of preincubation with atorvastatin, electroporation of steroidogenic cells should be performed at high voltage and combined with a calcium supply.
Topics: Anticholesteremic Agents; Antineoplastic Agents; Apoptosis; Atorvastatin; Calcium; Cell Membrane; Cell Membrane Permeability; Cell Proliferation; Cholesterol; Electrochemotherapy; Electroporation; Humans; Neoplasms; Tumor Cells, Cultured
PubMed: 34681903
DOI: 10.3390/ijms222011245 -
Current Drug Delivery 2022Lung cancer is one of the main causes of mortality globally. This research paper aims a the development of inhaled nanotechnology for lung cancer to deliver an...
OBJECTIVE
Lung cancer is one of the main causes of mortality globally. This research paper aims a the development of inhaled nanotechnology for lung cancer to deliver an atorvastatin calcium compound, for lung cancer, capable of reaching the tumor site directly via inhalation.
METHODS
Atorvastatin calcium micellar nanoparticles (ATO-NPs) encapsulated with Pluronic F-127 and polyvinyl alcohol (PVA) were manufactured utilizing the solvent and anti-solvent precipitation technique. The physicochemical features of the formulation were evaluated in terms of their physicochemical characteristics using Fourier transform infrared spectroscopy, differential scanning calorimetry, and dynamic light scattering. Additionally, the Andersen Cascade impactor was used at 15 L/minutes to assist in the aerosols performances of the formulation. The ATO-NPs formula's cell viability was tested in vitro using the A549 non-small cell lung cancer cell type.
RESULTS
Transmission electron microscopy was utilized to determine the ATO-NPs particle morphology, demonstrating a spherical shape with a smooth surface. The fine particle fraction of the aerosol produced was 62.70 ± 1.18%. This finding suggests that atorvastatin micellar nanoparticles are suitable for medication administration by inhalation with a wide particle size dispersion. Moreover, it was found in vitro that concentrations of up to 21 μg/mL of the atorvastatin nanoparticles were safe and non-toxic in the cell model.
CONCLUSION
This study found that atorvastatin micellar nanoparticles for inhalation could potentially be used for lung cancer treatment.
Topics: Administration, Inhalation; Atorvastatin; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Nanoparticles; Particle Size; Respiratory Aerosols and Droplets
PubMed: 35473526
DOI: 10.2174/1567201819666220426091500