HMG-CoA Research Articles

The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Due to its uncertain pathogenesis, there is currently no treatment available for AD. Increasing evidences have linked cellular senescence to AD, although the mechanism triggering cellular senescence in AD requires further exploration. To investigate the involvement of cellular senescence in AD, we explored the effects of cadmium chloride (CdCl2) exposure, one of the potential environmental risk factors for AD, on neuron senescence in vivo and in vitro. β-amyloid (Aβ) and tubulin-associated protein (tau) pathologies were found to be enhanced by CdCl2 exposure in the in vitro models, while p53/p21/Rb cascade-related neuronal senescence pathways were activated. Conversely, the use of melatonin, a cellular senescence inhibitor, or a cadmium ion chelator suppressed CdCl2-induced neuron senescence, along with the Aβ and tau pathologies. Mechanistically, CdCl2 exposure activated the suppressor enhancer Lin-12/Notch 1-like (SEL1L)/HMG-CoA reductase degradation 1 (HRD1)-regulated endoplasmic reticulum-associated degradation (ERAD), which enhanced the ubiquitin degradation of sigma-1 receptor (SigmaR1) by specifically recognizing its K142 site, resulting in the activation of the p53/p21/Rb pathway via the induction of Ca2+ dyshomeostasis and mitochondrial dysfunction. In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2–73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice. Consequently, the present study revealed a novel senescence-associated regulatory route for the SEL1L/HRD1/SigmaR1 axis that affects the pathological progression of CdCl2 exposure-associated AD. CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy.

Statin treatment reduces leucine turnover, but does not affect endogenous production of beta-hydroxy-beta-methylbutyrate (HMB)

BackgroundStatins, or hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, are one of the most commonly prescribed medications for lowering cholesterol. Myopathic side-effects ranging from pain and soreness to critical rhabdomyolysis are commonly reported and often lead to discontinuation. The pathophysiological mechanism is, in general, ascribed to a downstream reduction of Coenzyme Q10 synthesis. HMG-CoA is a metabolite of leucine and its corresponding keto acid α-ketoisocaproic acid (KIC) and β-hydroxy-β-methylbutyrate (HMB), however, little is known about the changes in the metabolism of leucine and its metabolites in response to statins. ObjectiveWe aimed to investigate if statin treatment has implications on the upstream metabolism of leucine to KIC and HMB, as well as on other branched chain amino acids (BCAA). Design12 hyperlipidemic older adults under statin treatment were recruited. The study was conducted as a paired prospective study. Included participants discontinued their statin treatment for 4 weeks before they returned for baseline measurements (before). Statin treatment was then reintroduced, and the participants returned for a second study day 7 days after reintroduction (after statin). On study days, participants were injected with stable isotope pulses for measurement of the whole-body production (WBP) of all BCAA (leucine, isoleucine and valine), along with their respective keto acids and HMB. ResultsWe found a reduced leucine WBP (22 %, p = 0.0033), along with a reduction in valine WBP (13 %, p = 0.0224). All other WBP of BCAA and keto acids were unchanged. There were no changes in the WBP of HMB. ConclusionsOur study shows that statin inhibition of HMG-CoA reductase has an upstream impact on the turnover of leucine and valine. Whether this impairment in WBP of leucine may contribute to the known pathophysiological side effects of statins on muscle remains to be further investigated.

Estimating the effect of lipid-lowering agents on novel subtypes of adult-onset diabetes.

The aims of the present study were to assess the effects of lipid-lowering drugs [HMG-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors] on novel subtypes of adult-onset diabetes through a Mendelian randomisation study. We first inferred causal associations between lipid-related traits [including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoproteins A-I, and apolipoproteins B] and novel subtypes of adult-onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid-lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL-C, were then utilised as proxies for the exposure of lipid-lowering drugs. Mendelian randomisation analysis was performed using summary data from genome-wide association studies of LDL-C, severe autoimmune diabetes, severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes. There was an association between HMGCR-mediated LDL-C and the risk of SIRD [odds ratio (OR)=0.305, 95% confidence interval (CI)=0.129-0.723; p=0.007], and there was an association of PCSK9-mediated LDL-C with the risk of SIDD (OR=0.253, 95% CI=0.120-0.532; p<0.001) and MOD (OR=0.345, 95% CI=0.171-0.696; p=0.003). Moreover, NPC1L1-mediated LDL-C (OR=0.109, 95% CI=0.019-0.613; p=0.012) and the increased expression of NPC1L1 gene in blood (OR=0.727, 95% CI=0.541-0.977; p=0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses. In summary, the different lipid-lowering medications have a specific effect on the increased risk of different novel subtypes of adult-onset diabetes.

Tolypocladium sinense Mycelium Polysaccharide Alleviates Obesity, Lipid Metabolism Disorder, and Inflammation Caused by High Fat Diet via Improving Intestinal Barrier and Modulating Gut Microbiota.

Tolypocladium sinense is a fungus isolated from Cordyceps. Cordyceps has some medicinal value and is also a daily health care product. This study explores the preventive effects of T. sinense mycelium polysaccharide (TSMP) on high-fat diet-induced obesity and chronic inflammation in mice. Here, the study establishes an obese mouse model induced by high-fat diet. In this study, the mice are administered TSMP daily basis to evaluate its effect on alleviating obesity. The results show that TSMP can significantly inhibit obesity and alleviate dyslipidemia by regulating the expression of lipid metabolism-related genes such as liver kinase B1 (LKB1), phosphorylated AMP-activated protein kinase (pAMPK), peroxisome proliferator activated receptor α (PPARα),fatty acid synthase (FAS), and hydroxymethylglutaryl-CoA reductase (HMGCR) in the liver. TSMP can increase the protein expression of zona occludens-1 (ZO-1), Occludin, and Claudin-1 in the colon, improve the intestinal barrier dysfunction, and reduce the level of serum LPS, thereby reducing the inflammatory response. 16S rDNA sequencing shows that TSMP alters the intestinal microbiota by increasing the relative abundance of Akkermansia, Lactobacillus, and Prevotellaceae_NK3B31_group, while decreasing the relative abundance of Faecalibaculum. The findings show that TSMP can inhibit obesity and alleviates obesity-related lipid metabolism disorders, inflammatory responses, and oxidative stress by modulating the gut microbiota and improving intestinal barrier.

A Study of the Relationship between Serum Magnesium Levels and Lipid Profile in Hypertensive patients on Diuretics

Hypertension (HTN) is a chronic universal health problem. It is considered an important changeable risk factor for morbidity and mortality. Diuretics are among the first-line medications for HTN treatment. Both thiazide-type diuretics and loop diuretics promote urinary loss of electrolytes such as magnesium. Magnesium has been studied for its important involvement in many physiological processes and biochemical pathways. It plays a significant role in regulating the activity of enzymes required in lipids and lipoproteins metabolism like HMG-CoA Reductase, lipoprotein lipase (LPL), and lecithin cholesterol acyl transferase (LCAT). It is well documented that dyslipidemia is a general threat to health and should be determined early to manage cardiovascular disease (CVD) and prevent its complications. The goal of the current study was to investigate the association between serum magnesium levels and lipid profile components in hypertensive patients on long-term diuretics therapy. The study was conducted on 50 adult hypertensive patients and 25 matched healthy subjects at Tishreen University Hospital (TUH) of Lattakia City in Syria. The study showed a statistically significant decrease in serum magnesium concentrations in the patients group (1.87±0.16mg/dl) versus the controls (2.40±0.41mg/dl) (P&lt;0.05). A significant negative correlation between magnesium and triglycerides, total cholesterol, LDL cholesterol was identified, while a significant positive correlation with HDL cholesterol was found. In conclusion, this study has showed that hypomagnesemia is related to increased levels of TC, LDL-c, TG and decreased levels of HDL-c, therefore, an increased risk of dyslipidemia in hypertensive patients on diuretics.

Diagnosis, Management, and Associated Comorbidities of Polycystic Ovary Syndrome: A Narrative Review.

Polycystic ovary syndrome (PCOS) is the most widespread and diverse endocrine health issue affecting many adolescent-aged women globally. It is the most frequent illness in reproductive-aged women. According to the Rotterdam criteria, two out of three elements: oligo-anovulation, hyperandrogenism, and polycystic ovaries (defined as having at least one ovary with an ovarian volume > 10 mL and/or 12 or more follicles measuring 2 to 9 mm in diameter) are present in PCOS. Conducted studies show epigenetics, environmental toxins, stress, and food as external factors as well as inflammation, oxidative stress, hyperandrogenism, insulin resistance, and obesity as internal factors related to PCOS. Although a portion of the mechanism associated with the occurrence of PCOS has been identified, there is still much to learn about the exact etiology and pathophysiology. The main debate covers the best ways to diagnose and treat this disease in adolescents. Early detection is crucial because of the disease's long-term effects on metabolic and reproductive health. Before beginning treatment for this group of young women, a firm diagnosis may not be made. Various criteria are used to diagnose PCOS patients. A person with PCOS has a chance of developing several comorbidities and health effects. PCOS patients are at risk of cardiac diseases, metabolic syndromes, resistance to insulin, infertility, and many more. There are numerous medications available for PCOS therapy that need a methodical approach. However, changing one's lifestyle should come first. There is proof in the support of the usage of several medications for PCOS, including mucolytic agents, Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, gliptins (oral diabetic medication), glucose-like peptide-1 receptor analogues, glitazones, and sodium-glucose cotransporter protein-2 (SGLT2) inhibitors. A comprehensive, systematic, schematic therapy approach is crucial for the treatment of PCOS.

Nano Formulation and Evaluation of Atorvastatin Mouth Dissolving Tablets

Atorvastatin calcium is an anti-hyperlipidemic drug that competitively inhibit HMG-CoA reductase and decrease production of cholesterol in liver. This statin derivative is highly metabolized in gut wall and liver so that it produces only 14% oral bioavailability. In this study we aim to improve the bioavailability of BCS II drug atorvastatin calcium in the formulation of mouth dissolving tablet, which enters the blood stream via facial, jugular artery and vein, by penetrating the lipid membrane when the tablet disintegrates. The Atorvastatin – chitosan nanoparticles was formulated by freeze drying of colloidal solution of nanoparticles. Super disintegrant like croscarmellose sodium, crospovidone, and sodium starch glycolate were added and tested for its dispersion properties. The prepared formulation shows enhanced rate of dissolution and may helpful by avoiding first pass metabolism and to achieve maximum bioavailability. Further the polymeric nano formulation (atorvastatin-chitosan nano particle) allows drug to penetrate much faster and dissolve the drug in saliva. Finally, the prepared formulation is evaluated by pre formulation studies, pre compression evaluation, post compression evaluation and the result of the study revealed that atorvastatin chitosan nanoparticles with size of 406 nm and PDI 0.246 had 118% dissolute in 10 min and shows enhance bioavailability.

Is cholesterol both the lock and key to abnormal transmembrane signals in Autism Spectrum Disorder?

Disturbances in cholesterol homeostasis have been associated with ASD. Lipid rafts are central in many transmembrane signaling pathways (including mTOR) and changes in raft cholesterol content affect their order function. Cholesterol levels are controlled by several mechanisms, including endoplasmic reticulum associated degradation (ERAD) of the rate limiting HMGCoA reductase. A new approach to increase cholesterol via temporary ERAD blockade using a benign bacterial toxin-derived competitor for the ERAD translocon is suggested.A new lock and key model for cholesterol/lipid raft dependent signaling is proposed in which the rafts provide both the afferent and efferent 'tumblers' across the membrane to allow 'lock and key' receptor transmembrane signals.

Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time-dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr-KO mice. Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β-oxidation and very high accumulation of long-chain (LC) acylcarnitines in both male and female mice. Gene expression and KO-related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole-body hypoglycaemia. Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.

Tendinopathies Associated with Statin Therapy in Patients with Dyslipidemia: Case Study Article Sidebar

Statins are considered the initial and first-line treatment in cardiovascular and atherosclerotic diseases, characterized by inhibiting HMG-CoA reductase. Some adverse effects associated with these drugs are injuries to the tendon structure including tenosynovitis, tendon and tendon rupture. The aim of this article is to evaluate the tendon structure by musculoskeletal ultrasound and to raise the question of whether chronic statin consumption in this patient with dyslipidemia is related to the appearance of tendinopathies. Methodology A cross-sectional descriptive observational study was carried out, focused on the evaluation of the incidence of tendinopathies in patients who have been using statins chronically. A case study approach was used, analysing in detail a female patient selected according to the established inclusion and exclusion criteria. The sample consisted of a patient who met the inclusion criteria: age between 45-60 years, chronic use of statins for more than 12 months, presentation of symptoms suggestive of tendinopathy. Patients with a history of musculoskeletal diseases prior to the start of treatment were excluded, and anyone with arthritis, chronic septic inflammatory processes, athletes, young patients, and those who did not want to participate in the study and did not agree to give informed consent were excluded. For data collection, 7 patients were selected, of which 1 only met the inclusion and acceptance criteria for the study, a clinical history was taken with exhaustive clinical evaluations of the selected patients, focused on the identification of tendinopathy symptoms and other possible risk factors, at the end a musculoskeletal ultrasound was carried out where possible tendon injuries were identified and characterized. evaluating tendon structure and its relationship to statin use. This methodology provides a detailed and structured approach to conducting research on the incidence of tendinopathies associated with statin use. Results During the clinical evaluation of this patient, symptoms associated with tendinopathy of the long portion of the biceps brachii on the right side were identified. The results of the musculoskeletal ultrasound confirmed the alterations in the structure of the tendon, finding tenosynovitis, significant peritendinous effusion and microruptures of the long portion of the biceps brachii not only on the affected side, but also on the contralateral side, which was asymptomatic for tendon pathology. In addition, not only was the biceps tendon modified, micro ruptures in the supraspinatus tendon and subacromial bursitis were observed. This patient had been taking atorvastatin 20mg every 24 hours in the mornings for 9 years and was not attributed with any mechanism of overuse injury that triggered multiple tendinopathies at the rotator cuff level.

Determination of Pharmacokinetic and Toxicological Parameters of Some Commonly Used Statin Group Drugs

Statins work as inhibitors of the HMG-CoA reductase enzyme and are the most commonly prescribed cholesterol-lowering drug group for people with cardiovascular disease or risk. This study aimed to determine the pharmacokinetic parameters and toxicities of conventional and new-generation cholesterol drugs such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin and pitavastatin. Absorption, distribution, metabolism, and excretion (ADME) parameters and toxicity predictions of drugs were made using in silico modeling, which gives faster results than animal experiments and does not involve any laboratory costs. In calculations made using structural similarity, compounds' pharmacokinetic properties and toxicity predictions are obtained based on previously known structure-activity data. The study results showed that the toxicity classifications of the drugs were 5 (LD: 5000 mg/kg) for atorvastatin and 6 (LD: 8939 mg/kg) for pravastatin, respectively. The toxicity classes were found to be 4 for all the other statin group drugs. The results showed that pravastatin had the lowest toxicity among investigated cholesterol drugs, while pitavastatin and fluvastatin had the highest toxic effects. Accordingly, it is recommended that the consequences of using pravastatin and atorvastatin, cholesterol drugs with lower toxicity classes, should be investigated more seriously in terms of minimum toxic substance intake for patient groups requiring high doses of medication.

The Toxicity and Biological Functions of Statins During Treatments

Cardiovascular morbidity and mortality are reduced by statins, which are drugs that lower cholesterol and reduce LDL-c. Statins function by competitively blocking the primary rate-limiting enzyme in HMG-CoA reductase, inhibiting it so that no substrate can enter and no HMG-CoA can be converted to mevalonic acid. Statins are by far the mainstay of majority and minority prevention of atherosclerotic cardiovascular disease, but they have also been linked to a variety of side effects. Statin therapy should be discontinued because of muscle symptoms associated with it and the development of new-onset type 2 diabetes as a side effect of statins is a serious issue and the pathogenesis of it is still unclear. This paper focuses on the biological function of statins and their toxicity, i.e. the mechanisms responsible for the adverse effects. It is intended to inform the study of the mechanisms of toxicity episodes of statins. Some of the mechanisms of toxicity onset of statins cannot be determined at this time, various patient populations could be studied in future studies to explore the side effects of statins.

Primary Sjögren’s syndrome independently promotes premature subclinical atherosclerosis

ObjectivesCardiovascular comorbidities are common in patients with autoimmune diseases. This study investigates the extent of subclinical atherosclerosis in patients with primary Sjögren’s syndrome (pSS). Correlations with clinical factors such as...

The Effect of Simvastatin on Thyroid Function in Experimental Autoimmune Thyroiditis Induced in Rats

Autoimmune thyroiditis or Hashimoto’s thyroiditis (HT): is the most common autoimmune thyroid disease. is characterized by marked lymphocytic infiltration and the presence of serum autoantibodies against Thyroid peroxidase (TPO) and Thyroglobulin (TG). HT is a prevalent cause of hypothyroidism in areas of the world where dietary iodine is sufficient. Genetic predisposition and cellular and humoral immunity play a role in thyroid autoimmune pathogenesis. Antithyroid antibodies are produced by interaction between APC, T cells, and B cells to fix complement. Thyroid tissue is more severely damaged by complement-dependent antibody-mediated cytotoxicity. Statins, the powerful inhibitors of HMG-CoA reductase have pleotropic effects including anti-inflammatory and immunomodulatory effects. In this current study, Experimental autoimmune thyroiditis was induced in twenty-four female Wistar rat. Simvastatin was given at a dose of 4mg/kg for 30 days. Thyroid autoantibodies and Thyroid hormones were measured by ELISA technique Results showed that Simvastatin reduced autoantibodies against TPO and TG. It also lowered serum level of TSH and increased serum level of T4. Due to the undesirable side effects associated with the current treatment options used in Autoimmune thyroiditis. Simvastatin might be a promising approach in the treatment of this disease.

OMEGA-3 POLYUNSATURATED FATTY ACIDS ADMINISTRATION IN PREVENTION OF POSTOPERATIVE ATRIAL FIBRILLATION DURING CORONARY ARTERY BYPASS GRAFT SURGERY

HighlightsThe appointment of omega-3 polyunsaturated fatty acids for the prevention of postoperative atrial fibrillation during coronary artery bypass grafting in patients with coronary artery disease requires a thorough analysis of the characteristics of a patient and an assessment of clinical and echocardiographic parameters, factors influencing surgical performance, inflammation, and oxidative stress. Moreover, the dosage of the drug impacts the risk of atrial fibrillation. Omega-3 polyunsaturated fatty acids in short-term therapy reduce the frequency of new episodes of this arrhythmia after the intervention, however, this effect is offset by the combined use of statins. AbstractThe article presents the available literature data on the effectiveness of the use of omega-3 polyunsaturated fatty acids in the prevention of postoperative atrial fibrillation in patients with coronary artery disease during coronary artery bypass grafting. Possible mechanisms of the drug’s antiarrhythmic action are highlighted, including its anti-inflammatory and antioxidant effects. The reasons for the decrease in the activity of omega-3 polyunsaturated fatty acids in combination with HMG-CoA reductase inhibitors are discussed.

Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase

Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4–2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to – 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4–2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4–2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4–2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.

Drug Target Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with significant clinical implications. The potential influence of lipid-lowering therapies, specifically PCSK9 inhibitors (PCSK9i) and HMG-CoA reductase inhibitors (statins), on AF risk remains a topic of interest. This mendelian randomization (MR) study aimed to elucidate the causal relationship between genetically predicted inhibition of PCSK9 and HMG-CoA reductase and the risk of AF. Methods: Utilizing publicly available, summary-level genome-wide association study data, we employed single-nucleotide polymorphisms associated with lower LDL-C levels as instruments for gene-simulated inhibition of PCSK9 and HMG-CoA reductase. Multiple MR techniques were applied to estimate the causal effects, and sensitivity analyses were conducted to validate the results. Results: Genetically predicted inhibition of PCSK9 demonstrated a reduced risk of AF, with an odds ratio (OR) of 0.92 (95% CI: 0.85–0.99, p = 0.01) using the inverse variance-weighted (IVW) method. In contrast, the inhibition of HMG-CoA reductase did not exhibit a statistically significant association with AF risk (IVW: OR = 1.11, 95% CI: 1.00–1.22, p = 0.05). Conclusion: Our MR study suggests that genetically predicted inhibition of PCSK9, but not HMG-CoA reductase, is associated with a lower risk of AF. These findings provide evidence for a causal protective effect of PCSK9i on AF and support the use of PCSK9i for AF prevention in patients with dyslipidemia. Further studies are needed to elucidate the mechanisms underlying the differential effects of PCSK9i and statins on AF and to confirm the clinical implications of our findings.

Early statin exposure influences cardiac and skeletal development with implications for ion channel transcriptomes in zebrafish

Statins, widely prescribed for cholesterol management by inhibiting HMG-CoA reductase in the cholesterol biosynthesis pathway, may also influence vertebrate development. In this study, we investigated the developmental effects of two widely used statins, atorvastatin (ATO) and pravastatin (PRA), on zebrafish offspring. For ATO, we administered doses classified as low (1 μM), medium (5 μM), and high (10 μM), while for PRA, the corresponding concentrations were set at low (18 μM), medium (180 μM), and high (270 μM). Our results showed significant reductions in birth and hatching rates, along with decreased body length in offspring at all ATO concentrations and medium to high PRA concentrations. A notable increase in malformation rates, especially in the spine and heart, was observed across all ATO treatments and in medium and high PRA groups. Additionally, we observed reduced heart contraction rates, decreased heart size, lower bone volumes, and diminished expression of mRNA osteogenic markers. Elevated venous sinus-artery bulb (SV-BA) ratios, increased thoracic area, and abnormal cartilage development were also prominent in all ATO-treated groups. Transcriptome analysis revealed alterations in genes predominantly associated with ion channels. These findings provide insights into the potential impacts of specific concentrations of statins on offspring development and highlight potential gene interactions with statins.

Abstract 5873: ERα coordinates with squalene synthase to confer statin resistance in lung cancer

Abstract Statins are widely used to treat hypercholesterolemia by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR). Accumulating evidence suggests that statins also have protective effects against cancer recurrence. However, the role of statins in preventing lung cancer and biomarkers for predicting statin treatment response remains lacking. This study analyzes molecular features that dictate statin sensitivity in lung cancer by correlating large-scale statin sensitivity data and basal gene expression in a collection of 125 lung cancer patients. We identified a gene signature associated with lovastatin sensitivity and showed that gene expression in mesenchymal molecular features, the cholesterol biosynthesis pathway, and estrogen receptor alpha (ERα) signaling were key determinants of lovastatin sensitivity in lung cancer cells. To this end, we further discovered that overexpression of a committed step enzyme in cholesterol biosynthesis farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), is capable of activating ERα and is associated with increased statin tolerance. In clinical specimens, overexpression of SQS positively correlated with nuclear expression of ERα in lung cancer patients, and the combination of SQS and ERα is a powerful prognostic predictor for lung cancer. Activation of the SQS-ERα signaling axis and epithelial-to-mesenchymal transition (EMT) status represents two important features in determining statin sensitivity in lung cancer. Keywords: Statin, cholesterol biosynthesis, squalene synthase, estrogen receptor α, Epithelial-mesenchymal transition Citation Format: Yi-Fang Yang. ERα coordinates with squalene synthase to confer statin resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5873.

Abstract 4126: The inhibitory effect of statins on distant metastasis and recurrence of endometrial cancer

Abstract Endometrial cancer (EC) is the most common gynecologic malignancy. The most common histological type is endometrioid endometrial cancer (EEC). While the majority of patients present with early-stage and low-grade EEC and have an excellent prognosis, a subset develops distant recurrence derived from EEC after initial treatment of the primary. However, the exact mechanism of distant metastasis and recurrence from EEC is still unclear. In addition, the lack of suitable pre-clinical models is a significant barrier to research for distant metastasis and recurrent cancer derived from EEC. Our preclinical EEC model, the ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/fPtenf/f; Mig-6d/dPtend/d), dramatically accelerates the development of EEC compared to single ablation of either gene. The ablation of both Mig-6 and Pten in the uterus (Pgrcre/+Mig-6f/f Ptenf/f; Mig-6d/dPtend/d mice) displayed distant metastases into the ovary, diaphragmatic skeletal muscle, lymph node, and lung. However, the Ptend/d mice exhibited endometrial cancer without distant metastases. After hysterectomy of EEC confined to uterus, Mig-6d/dPtend/d mice exhibited recurrent EEC in abdomen and lung. To identify prognostic factors for distant metastatic and recurrent EEC, we performed transcriptomic analysis in endometrial hyperplasia, a precancerous condition, from Ptend/d and Mig-6d/dPtend/d mice. Our transcriptomic analysis identified that cholesterol biosynthesis was the most significantly activated pathway in Mig-6d/dPtend/d mice compared to Ptend/d mice. Statins, also known as HMG-CoA reductase inhibitors, are the most common cholesterol-lowering drugs. We evaluated the effect of atorvastatin on tumorigenesis and recurrence of EEC. Mig-6d/dPtend/d mice treated with atorvastatin displayed significant reduction of tumor size compared to vehicle treated group. For vehicle-treated group, our pathological analysis revealed EEC outside the uterus, therefore EEC had disseminated to involve the ovary, diaphragmatic skeletal muscle, lymph node, and lung. However, EEC was confined to the uterus in the atorvastatin treated group. Furthermore, atorvastatin treatment reduced the rate of recurrent EEC development. This data demonstrated that atorvastatin has a remarkable inhibitory effect on metastasis and recurrence of EEC in Mig-6d/d Ptend/d mice. Our results suggest that statins suppress development of distant metastasis and recurrence in mouse models of EEC with Pten and Mig-6 deficiency by inhibiting cholesterol biosynthesis. Citation Format: Keun Cheon Kim, Jung Yoon Yoo, Russell R Broaddus, Eunhee M Jeong, Mark I Hunter, Tae Hoon Kim, Jae-Wook Jeong. The inhibitory effect of statins on distant metastasis and recurrence of endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4126.