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Biomedicine & Pharmacotherapy =... Oct 2023As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular...
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.
Topics: Mice; Animals; Atorvastatin; Endothelial Cells; Ubiquitination; Ubiquitin-Protein Ligases; Mice, Knockout; Hypertension
PubMed: 37557013
DOI: 10.1016/j.biopha.2023.115228 -
Yonsei Medical Journal Mar 2023Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with diabetes and/or dyslipidemia. However, statins and antidiabetic agents have opposite pharmacological effects, because statins, particularly atorvastatin and rosuvastatin, impair glucose homeostasis, increasing the risk of new-onset diabetes, whereas antidiabetic drugs improve glycemic homeostasis. The aim of this study was to investigate the effect of atorvastatin, rosuvastatin, and pitavastatin on glucose homeostasis in patients with type 2 diabetes mellitus (T2DM) and dyslipidemia during stable treatment with hypoglycemic drugs.
MATERIALS AND METHODS
The study was conducted as a pilot, prospective, randomized, open label, parallel group with blinded-endpoints (PROBE) study. Of 180 recruited patients with T2DM and dyslipidemia, 131 were randomized to atorvastatin (n=44), rosuvastatin (n=45), and pitavastatin (n=42) and treated for 6 months.
RESULTS
Fasting plasma glucose (FPG) marginally decreased in patients assigned to atorvastatin (-3.5 mg/dL, =0.42) and rosuvastatin (-6.5 mg/dL, =0.17), while it decreased much more in patients treated with pitavastatin (-19.0 mg/dL, <0.001). Mean glycated hemoglobin A1c (HbA1c ) values remained unchanged during treatment with atorvastatin (-0.10%, =0.53) and rosuvastatin (0.20%, =0.40), but were significantly reduced with pitavastatin (-0.75%, =0.01). Atorvastatin, rosuvastatin, and pitavastatin significantly lowered (<0.001) plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and triglycerides, while high-density lipoprotein-cholesterol (HDL-C) levels increased significantly (=0.04) only in the pitavastatin group.
CONCLUSION
The results of the present study suggest that pitavastatin affects FPG and HbA1c less than atorvastatin and rosuvastatin in patients with T2DM and concomitant dyslipidemia. Lipid-lowering efficacies were not significantly different among the three statins, with the exception of HDL-C, which increased significantly with pitavastatin. Although the pharmacological mechanism of pitavastatin on glucose homeostasis in patients with T2DM during stable antidiabetic therapy is not known, it can be assumed that pitavastatin has less drug interaction with hypoglycemic agents or that it increases plasma levels of adiponectin.
Topics: Humans; Atorvastatin; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dyslipidemias; Glucose; Glycated Hemoglobin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Prospective Studies; Pyrroles; Rosuvastatin Calcium; Treatment Outcome
PubMed: 36825343
DOI: 10.3349/ymj.2022.0287 -
Medicine Jun 2017The high recurrent rate of chronic subdural hematoma (CSDH) has consistently confused the neurosurgeons, and the role of atorvastatin in the management of CSDH has... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The high recurrent rate of chronic subdural hematoma (CSDH) has consistently confused the neurosurgeons, and the role of atorvastatin in the management of CSDH has remained unclear over past decade, and atorvastatin seems to be a safe and cost-effective treatment to CSDH. Therefore, it is necessary to conduct a systematic review to discuss the effect of atorvastatin in CSDH.
METHOD
We searched the PubMed, EMBASE, Cochrane Library, and the China Biology Medicine disc, up to March 2017, for published studies on the effects of atorvastatin in the management of CSDH, and reviewers performed a brief qualitative descriptive analysis of atorvastatin's efficacy in the management of CSDH.
RESULTS
Three eligible studies were included in this systematic review. Results indicated that atorvastatin accelerated hematoma absorption, decreased recurrence risk, and surgical requirement.
CONCLUSION
Limited evidence suggests that oral atorvastatin may be beneficial in the management of CSDH. Further high-quality studies focused on dosage, duration, hematoma size are needed to further elucidate the role of atorvastatin in the management of CSDH.
Topics: Administration, Oral; Atorvastatin; Hematoma, Subdural, Chronic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 28658127
DOI: 10.1097/MD.0000000000007290 -
Free Radical Biology & Medicine Nov 2023A novel circRNA named circSQSTM1 (hsa_circRNA_075320) was screened out in atorvastatin (ATV) stimulated endothelial cells (ECs) by our group. Considering the...
A novel circRNA named circSQSTM1 (hsa_circRNA_075320) was screened out in atorvastatin (ATV) stimulated endothelial cells (ECs) by our group. Considering the anti-atherosclerotic function of ATV, we hypothesized the circSQSTM1 could protect ECs functions in AS progression. The effects of circSQSTM1 on ECs inflammation, oxidative stress and autophagy were measured by qRT-PCR, Western blotting, monocyte-endothelial adhesion assay, dichloro-dihydro-fluorescein diacetate and mCherry-GFP-LC3 labeling. A luciferase reporter assay, RNA immunoprecipitation, MS2-tagging system and fluorescence in situ hybridization were performed to identify the biological functions of circSQSTM1. The partial left carotid artery ligation model and atherosclerosis model were established to analyze the effects of circSQSTM1 on atherosclerosis progression in vivo. Our results revealed that ATV induced the accumulation of circSQSTM1 in ECs via suppressing m6A modified degradation. In the cytoplasm, circSQSTM1 could relieve Sirt1 by competitively sponging miR-23b-3p. In the nucleus, circSQSTM1 directly interacts with eIF4A3 and promoting the efficient nuclear export of FOXO1 mRNA, which encodes FOXO1 transcription factor to directly activate Sirt1 promoter activity. Hence, circSQSTM1 reduced inflammation, inhibited oxidative stress and promoted autophagy by upregulating Sirt1 in ECs. Moreover, circSQSTM1 overexpression in ECs attenuated the progression of atherosclerosis in ApoE mice. Taken together, the unique noncoding RNA known as circSQSTM1 took a protective role to the ECs in atherosclerosis.
Topics: Animals; Mice; Atherosclerosis; Endothelial Cells; In Situ Hybridization, Fluorescence; Inflammation; RNA, Circular; Sirtuin 1; Atorvastatin
PubMed: 37865306
DOI: 10.1016/j.freeradbiomed.2023.10.398 -
BMC Complementary Medicine and Therapies Nov 2023Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors....
BACKGROUND
Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors. Atorvastatin is mainly used for the treatment of atherosclerosis in clinic. A large number of studies show that atorvastatin may produce anti-tumor activities. This study aimed to predict the common targets of atorvastatin against atherosclerosis and non-small cell lung cancer (NSCLC) based on network pharmacology.
METHODS
The target genes of atherosclerosis and NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The disease-target-component model map and the core network were obtained using Cytoscape 3.7.1. The MTS and wound healing assay were used to detect the effect of atorvastatin on cell viability and migration of A549 cells. The expression of potential common target genes of atorvastatin against atherosclerosis and NSCLC were confirmed in A549 cells and lung cancer tissues of patients.
RESULTS
We identified 15 identical pathogenic genes, and four of which (MMP9, MMP12, CD36, and FABP4) were considered as the key target genes of atorvastatin in anti-atherosclerosis and NSCLC. The MTS and wound healing assays revealed that atorvastatin decreased A549 cells migration significantly. Atorvastatin markedly decreased the expression of MMP9, MMP12, CD36, and FABP4 in A549 cells and patients were treated with atorvastatin.
CONCLUSIONS
This study demonstrated 15 common pathogenic genes in both atherosclerosis and NSCLC. And verified that MMP 9, MMP 12, CD 36 and FABP 4 might be the common target genes of atorvastatin in anti-atherosclerosis and NSCLC.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Matrix Metalloproteinase 9; Atorvastatin; Matrix Metalloproteinase 12
PubMed: 37978381
DOI: 10.1186/s12906-023-04255-7 -
Revista Medica Del Instituto Mexicano... Oct 2023Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Atorvastatin has been used in the management of dyslipidemia and little is known about the efficacy and safety of high-dose atorvastatin administration for secondary prevention of Major Cardiovascular Events (MACE).
OBJECTIVE
To evaluate the impact of high-dose atorvastatin on secondary prevention of MACE and adverse events.
MATERIAL AND METHODS
A systematic review and meta-analysis of Pubmed, Embase, Bireme and Cochrane Library Plus databases was performed, with a time scope from 1990 to July 2022. Six randomized clinical trials were included with a total of 29,333 patients who were treated with 80 mg, 10 mg or placebo doses of Atorvastatin where the main outcomes evaluated were Major Cardiovascular Events (MACE), mortality and treatment safety.
RESULTS
In the comparative study between the use of Atorvastatin 80 mg and other therapies, a relative risk (RR) of 0.8 (95%CI 0.69-0.92) was found, representing a 20% reduction in risk (RRR) and a number needed to treat (NNT) of 30-55. In the analysis of adverse effects, an RR of 2.37 (95% CI 0.86-6.53) and a number needed to harm (NNH) of 14-19 were observed. The use of 80 mg atorvastatin is associated with similar adverse events at lower doses.
CONCLUSIONS
The use of atorvastatin 80 mg is effective in the secondary prevention of Major Cardiovascular Event (MACE). The drug has adverse events that should be taken into account in secondary prevention.
Topics: Humans; Atorvastatin; Cardiovascular Diseases
PubMed: 37934798
DOI: 10.5281/zenodo.8319748 -
Asian Pacific Journal of Cancer... Mar 2022Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells....
OBJECTIVE
Atorvastatin is commonly used as a lipid lowering drug. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells. Among the statins, atorvastatin, and in cancers, breast malignancies have received less attention in preclinical investigations. In order to enhance the efficacy of cancer treatment, adjuvant, less expensive therapeutic strategies have been recently noticed. In this case, we investigated the in-vitro effect of atorvastatin on viability and migration of MCF7 breast cancer cell line.
METHODS
We tested the cytotoxicity of atorvastatin on breast cancer cells survival by MTT assay. Annexin-V / PI staining and then flow cytometry of cancer cells in addition to quantitative real-time PCR tests quantified the apoptosis and necrosis of cancer cells. We figured out the impact of atorvastatin on cancer cell migration capability through scratch-wound healing assay and transwell migration examination. Inverted light microscope and fluorescent imaging displayed the morphological changes following treatment of MCF7 cells with atorvastatin.
RESULT
We resulted that atorvastatin can trigger MCF7 cancer cells to undergo necrosis and caspase-dependent apoptosis based on the viable/dead cell number, mitotic cell cycle, gene expression, and morphological assays. The results were dose- and time-dependent and the half- maximal inhibitory concentration of atorvastatin for cancer cells' viability inhibition was 9.1 μM/L(nM/mL). Moreover, the migration of MCF7 cells were inhibited in the treated group as we figured out in two- and three-dimensional migration methods.
CONCLUSION
In-vitro inspection of drug-cancer cell interactions paves the way for future in-vivo research studies. These in-vitro results revealed that atorvastatin has anti-viability and anti-migration effects on breast cancer cells.
Topics: Apoptosis; Atorvastatin; Breast Neoplasms; Cell Movement; Female; Humans; MCF-7 Cells
PubMed: 35345358
DOI: 10.31557/APJCP.2022.23.3.867 -
Advances in Rheumatology (London,... Dec 2022Statins have long been extensively prescribed as effective lipid-lowering agents, but statins have also been recognized as novel immunomodulators in recent years. This...
BACKGROUND
Statins have long been extensively prescribed as effective lipid-lowering agents, but statins have also been recognized as novel immunomodulators in recent years. This study was designed to investigate the immunomodulatory effects of atorvastatin on lupus-prone MRL/lpr mice.
METHODS
A total of 30 8-week-old female MRL/lpr mice were randomly divided into three groups and orally administered vehicle, atorvastatin orhydroxychloroquine sulfate for 11 weeks. In vivo, the effects of atorvastatin on the survival rate, renal function and spleen index in MRL/lpr mice were examined. Ex vivo, splenic B-cell proliferation was assessed by a Cell Counting Kit-8.
RESULTS
Oral atorvastatin failed to prolong survival time, or reduce the levels of proteinuria, or serum anti-dsDNA antibody and complement proteins (C3, C4). Histologically, no significant improvement by atorvastatin was observed in the pathological manifestations of renal damage, while hydroxychloroquine sulfate significantly improved glomerular injury. Ex vivo, atorvastatin suppressed the proliferation of splenic B lymphocytes.
CONCLUSION
Oral atorvastatin monotherapy had no therapeutic effects on MRL/lpr mice, whereas atorvastatin inhibited splenic B-cell proliferation in vitro, suggesting that atorvastatin has a potential therapeutic effect on systemic lupus erythematosus.
Topics: Mice; Animals; Female; Humans; Mice, Inbred MRL lpr; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lupus Erythematosus, Systemic
PubMed: 36471414
DOI: 10.1186/s42358-022-00282-z -
Chemical & Pharmaceutical Bulletin 2014The aim of the present study was to investigate the effect of Soluplus® on the solubility of atorvastatin calcium and to develop a solid dispersion formulation that can...
The aim of the present study was to investigate the effect of Soluplus® on the solubility of atorvastatin calcium and to develop a solid dispersion formulation that can improve the oral bioavailability of atorvastatin calcium. We demonstrated that Soluplus® increases the aqueous solubility of atorvastatin calcium. Several solid dispersion formulations of atorvastatin calcium with Soluplus® were prepared at various drug : carrier ratios by spray drying. Physicochemical analysis demonstrated that atorvastatin calcium is amorphous in each solid dispersion, and the 2 : 8 drug : carrier ratio provided the highest degree of sustained atorvastatin supersaturation. Pharmacokinetic analysis in rats revealed that the 2 : 8 dispersion significantly improved the oral bioavailability of atorvastatin. This study demonstrates that spray-dried Soluplus® solid dispersions can be an effective method for achieving higher atorvastatin plasma levels.
Topics: Administration, Oral; Animals; Atorvastatin; Biological Availability; Desiccation; Heptanoic Acids; Male; Polyethylene Glycols; Polyvinyls; Pyrroles; Rats; Rats, Sprague-Dawley; Solubility; Water
PubMed: 24881660
DOI: 10.1248/cpb.c14-00030 -
International Journal of Nanomedicine 2019Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent...
BACKGROUND
Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity.
MATERIALS AND METHODS
Liposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE) mice.
RESULTS
Targeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity.
CONCLUSION
Both in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Atorvastatin; Cell Death; Cell Survival; Chemokine CCL2; Curcumin; Drug Synergism; E-Selectin; Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Ligands; Lipids; Liposomes; Mice, Knockout; Particle Size; Static Electricity
PubMed: 30697048
DOI: 10.2147/IJN.S189819