Cardiovascular Toxicology最新文献

{"title":"Exercise Training After Myocardial Infarction Enhances Endothelial Progenitor Cells Function via NRG-1 Signaling.","authors":"Huai Huang, Guoqiang Huang, Ruojun Li, Liqin Wei, Zhu Yuan, Weiqiang Huang","doi":"10.1007/s12012-025-09967-5","DOIUrl":"10.1007/s12012-025-09967-5","url":null,"abstract":"<p><p>Vascular regeneration after myocardial infarction (MI) is essential to improve myocardial ischemia, delay post-infarction ventricular remodeling, and improve the long-term prognosis of MI. Endothelial progenitor cells (EPCs) play important roles in the functional repair and homeostatic maintenance of the vascular endothelium. Exercise training stimulates EPC mobilization and increases the number of circulating EPCs, which has beneficial effects on the restoration of vascular integrity and hemodynamic reconstitution. After post-MI exercise training, cardiac function, the myocardial infarct area, and capillary density in the peri-infarct zone were measured. Bone marrow-derived EPCs were isolated from mice to measure the proliferation, migration, and in vitro angiogenesis of EPCs after myocardial infarction exercise. The expression of NRG-1/ErbB4 signaling factor and related proteins in downstream PI3K/AKT signaling pathway were detected, and the level of autocrine NRG-1 in EPCs was detected. Post-MI resistance training, aerobic exercise training, and combined exercise training increased EPC mobilization and proliferation, migration, and tube-forming capacity, promoted myocardial vascular regeneration, improved cardiac function, and reduced infarct size. Exercise training upregulated NRG-1 expression in EPCs, and NRG-1/ErbB4 signaling activated the downstream PI3K/Akt signaling pathway. Moreover, EPCs may have a positive feedback autocrine loop with NRG-1 to improve the function of EPCs and promote vascular repair and regeneration in mice with MI. Exercise training after MI promotes the function of bone marrow-derived EPCs through NRG-1/ErbB4/PI3K/AKT signaling, thus exerting a role in angiogenesis.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"411-426"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnancy and Postpartum Effects of Electronic Cigarettes on Maternal Health and Vascular Function in the Fourth Trimester.","authors":"Amber Mills, Duaa Dakhlallah, Anand Ranpara, W Travis Goldsmith, Paul D Chantler, Yue-Wern Huang, Jonathan Boyd, I Mark Olfert","doi":"10.1007/s12012-025-09961-x","DOIUrl":"10.1007/s12012-025-09961-x","url":null,"abstract":"<p><p>Pregnancy is a vulnerable time with significant cardiovascular changes that can lead to adverse outcomes, which can extend into the postpartum window. Exposure to emissions from electronic cigarettes (Ecig), commonly known as \"vaping,\" has an adverse impact on cardiovascular function during pregnancy and post-natal life of offspring, but the postpartum effects on maternal health are poorly understood. We used a Sprague Dawley rat model, where pregnant dams are exposed to Ecigs between gestational day (GD)2-GD21 to examine postpartum consequences. Litter and dam health were monitored during the weaning period, and maternal vascular and endocrine function were assessed after weaning. Exposure to Ecig emissions during pregnancy led to fetal losses (i.e., reabsorption in utero) and reduced survival of pups during weaning compared to controls (air-exposed dams). We find that maternal vaping during pregnancy, with or without nicotine (or flavoring) results in maternal vascular and hormonal dysfunction (i.e., reduced prolactin, increased expression of sirtuin 1 deacetylase in the brain). Both 5 and 30W Ecig aerosol exposures resulted in significant impairment of middle cerebral artery reactivity to acetylcholine-mediated dilation (decreasing ~ 22 and ~ 50%, respectively). We also observed an increase in the number of extracellular vesicles (EVs) in plasma from 30-W group that persists up to 3-week postpartum and that these EVs impaired endothelial cell function when applied to in vitro and ex vivo assays. Our data suggest (1) Ecig vaping, even without nicotine or flavorings, during pregnancy alters maternal circulating factors that influence maternal and fetal health, (2) circulating EVs may contribute to the etiology of vascular dysfunction, and (3) that the window for recovery from vascular dysfunction in the dam is likely to be longer than the exposure window.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"325-340"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF146 Alleviates Myocardial Ischemia/Reperfusion Injury by Regulating the Ubiquitination-Mediated Degradation of DAPK1 to Inhibit Ferroptosis.","authors":"Xiangdong Qiu, Pengfei Yan, Qingyu Zhao, Lehong Yuan","doi":"10.1007/s12012-025-09972-8","DOIUrl":"10.1007/s12012-025-09972-8","url":null,"abstract":"<p><p>Ring finger protein 146 (RNF146) participates in regulating ferroptosis and ferroptosis is involved in myocardial ischemia/reperfusion injury (MI/RI). However, the effects and mechanisms of RNF146 in MI/RI are still unclear. TTC, H&E, IHC, DHE stainings, and echocardiography technology were used to determine the myocardial infarction area, pathological injury, level of RNF146, ROS, and cardiac function parameters, respectively. CCK-8 was employed to determine the cell viability. The corresponding kits, RT-qPCR, and western blot were adopted to determine the levels of CK-MB, LDH, Fe²⁺, MDA, ROS, gene expression levels of RNF146 and death-associated protein kinase 1 (DAPK1), protein expression levels of RNF146, DAPK1, GPX4, FTH1, and ACSL4. Co-immunoprecipitation, cycloheximide tracking, and ubiquitination assays to investigate the relationship between RNF146 and DAPK1. Ferroptosis occurred in mice with MI/RI and inhibiting ferroptosis could alleviate MI/RI. Moreover, the expression of RNF146 is down-regulated in MI/RI, and overexpression of RNF146 can inhibit H/R-induced ferroptosis of cardiomyocytes. Mechanistically, RNF146 promotes ubiquitination and degradation of DAPK1. In addition, the effects of overexpressed RNF146 in alleviating MI/RI were effectively reversed by overexpressing DAPK1. This study demonstrated that RNF146 alleviates MI/RI by facilitating the ubiquitylation-mediated degradation of DAPK1 to reduce ferroptosis.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"427-440"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETV5-Mediated Transcriptional Repression of DDIT4 Blocks Macrophage Pro-Inflammatory Activation in Diabetic Atherosclerosis.","authors":"Lili Shi, Tingting Sun, Di Huo, Lin Geng, Chao Zhao, Wenbo Xia","doi":"10.1007/s12012-024-09956-0","DOIUrl":"10.1007/s12012-024-09956-0","url":null,"abstract":"<p><p>Atherosclerosis risk is elevated in diabetic patients, but the underlying mechanism such as the involvement of macrophages remains unclear. Here, we investigated the underlying mechanism related to the pro-inflammatory activation of macrophages in the development of diabetic atherosclerosis. Bioinformatics tools were used to analyze the macrophage-related transcriptome differences in patients with atherosclerosis and diabetic mice. LDLR^-/- mice with DDIT4 depletion were generated and fed a Western diet to induce atherosclerosis. DDIT4 expression was elevated in diabetic mice and patients with atherosclerosis. Macrophage proinflammatory factors F4/80, Il-6, and TNFα were reduced in DDIT4^-/-LDLR^-/- mice and necrotic areas were decreased in the aortic root. Atherosclerotic plaque stability was increased in DDIT4^-/-LDLR^-/- mice, as evidenced by increased collagen and smooth muscle cell content. DDIT4, regulated by ETV5, acted on macrophages, affecting lipid accumulation, migration capacity, and pro-inflammatory responses. Knockdown of ETV5 increased expression of DDIT4 and pro-inflammatory factors in macrophages, increased necrotic core area in the aortic root, and decreased stability of atherosclerotic plaques in mice, which was abated by DDIT4 knockdown. The findings provide new insight into how diabetes promotes atherosclerosis and support a model wherein loss of ETV5 sustains transcription of DDIT4 and the pro-inflammatory activation of macrophages.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"379-394"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM21 Promotes Endothelial Cell Activation via Accelerating SOCS3 Ubiquitination Degradation in Atherosclerosis.","authors":"Zhenxuan Hao, Yihuan Wang, Linlin Chen, Yanjun Zhou, Dezhou Fang, Wenxiang Yao, Lili Xiao, Yanzhou Zhang","doi":"10.1007/s12012-025-09965-7","DOIUrl":"10.1007/s12012-025-09965-7","url":null,"abstract":"<p><p>Activated endothelial cells play an important role in the beginning of atherosclerotic disease by secreting various proteins and inflammatory cytokines. Ubiquitination is one of the most common post-translational changes in cells. However, the role and mechanisms of ubiquitination in endothelial cell activation remain poorly understood. In this study, we identified TRIM21 as an E3 ubiquitin ligase with increased expression in atherosclerotic disease and activated endothelial cells. Knockdown of TRIM21 resulted in reduced secretion of inflammatory factors and attenuated the pyroptosis of endothelial cells, inhibiting the progression of atherosclerosis. Mechanistically, TRIM21 could bind and ubiquitinate SOCS3, thereby enhancing NLRP3-mediated pyroptosis. Taken together, we found that endothelial TRIM21 activated the JAK/STAT3 pathway by degrading SOCS3, which in turn promoted NLRP3-mediated pyroptosis and aggravated atherosclerosis, revealing that TRIM21 may be a promising treatment target for the medical management of atherosclerosis.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"395-410"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking, Alcohol Consumption, and Atrial Fibrillation: Mendelian Randomization Study.","authors":"Xuejiao Ye, Qian Wu, Qianyu Lv, Xinzheng Hou, Yingtian Yang, Chenyan Yang, Shihan Wang","doi":"10.1007/s12012-025-09964-8","DOIUrl":"10.1007/s12012-025-09964-8","url":null,"abstract":"<p><p>Smoking, secondhand smoke exposure, and alcohol consumption are significant risk factors that contribute to an increased global burden of cardiovascular diseases. However, the casual relationship between smoking, passive smoking, alcohol consumption, and atrial fibrillation (AF) remains uncertain. Conventional observational studies are difficult to draw conclusion on high-quality causality. To elucidate the association between smoking, secondhand smoke exposure, alcohol consumption, and AF, we conducted this two-sample Mendelian randomization (MR) analysis. Smoking encompasses current tobacco smoking, ever-smoked, and light smokers, with light smokers being defined as at least 100 smokes in lifetime, as well as secondhand smoke exposure, which is characterized by workplace had a lot of cigarette smoke from other people smoking: Often. Alcohol consumption encompasses diagnoses-secondary ICD10: Z72.1 Alcohol use and the frequency of alcohol intake. Genetic variants associated with smoking and alcohol consumption were obtained from the IEU Open GWAS project and subsequently selected as instrumental variables (IVs). The corresponding variants associated with AF were also retrieved from the IEU Open GWAS project. The primary MR method utilized was the inverse-variance weighted (IVW). To assess the robustness of our results, multiple supplementary methods were utilized, including the weighted median (WM), MR-Egger regression, MR-PRESSO, MR-Egger intercept test, and the leave-one-out method. A reverse MR analysis was also conducted to determine the potential existence of reverse causality. Genetic predictions indicate a causal relationship between active smoking (current tobacco smoking, P_-val = 0.019, OR: 1.413, 95% CI = 1.058-1.888; ever smoked, P_-val = 0.049, OR: 1.355, 95% CI = 1.001-1.834; light smokers, P_-val = 0.001, OR: 1.444, 95% CI = 1.154-1.806) and AF. No causal association was found between secondhand smoke exposure, alcohol consumption phenotypes, and AF. Additionally, the reverse MR analysis did not reveal any evidence of reverse causality from AF to active smoking. This study provides MR evidence supporting a causal association between active smoking and AF. The significance of smoking cessation is underscored by its potential to prevent or mitigate the risk of AF. Furthermore, the impact of secondhand smoke exposure and alcohol consumption on AF, as well as the causality among these factors, warrants further investigation.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"341-353"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoxyl Sulfate Induces Ventricular Arrhythmias Attenuated by Secretoneurin in Right Ventricular Outflow Tract Cardiomyocytes.","authors":"Yuan Hung, Chen-Chuan Cheng, Yen-Yu Lu, Shih-Yu Huang, Yao-Chang Chen, Fong-Jhih Lin, Wei-Shiang Lin, Yu-Hsun Kao, Yung-Kuo Lin, Shih-Ann Chen, Yi-Jen Chen","doi":"10.1007/s12012-025-09963-9","DOIUrl":"10.1007/s12012-025-09963-9","url":null,"abstract":"<p><p>Ventricular arrhythmias (VAs) are major causes of sudden cardiac death in chronic kidney disease (CKD) patients. Indoxyl sulfate (IS) is one common uremic toxin found in CKD patients. This study investigated whether IS could induce VAs via increasing right ventricular outflow tract (RVOT) arrhythmogenesis. Using conventional microelectrodes and whole-cell patch clamps, we studied the action potentials (APs) and ionic currents of isolated rabbit RVOT tissue preparations and single cardiomyocytes before and after IS (0.1 and 1.0 μM). Calcium fluorescence imaging was performed in RVOT cardiomyocytes treated with and without IS (1.0 μM) to evaluate the calcium transient and the calcium leak. In rabbit RVOT tissues, IS (0.1 and 1.0 μM) attenuated the contractility and shortened the AP durations in a dose-dependent manner. In addition, IS (0.1 and 1.0 μM) enhanced the pro-arrhythmia effects of isoproterenol (ISO, 1.0 μM) and rapid ventricular pacing in RVOT (before versus after ISO, 25% versus 83%, N = 12). In RVOT cardiomyocytes, IS (1.0 μM) significantly decreased the L-type calcium currents but increased the sodium-calcium exchanger and sodium window currents. Cardiomyocytes treated with IS (1.0 μM) had lower calcium transients but higher diastolic calcium and calcium leak than those without IS treatment. Pretreatment with secretoneurin (SN, 30 nM, a potent neuropeptide, suppressing CaMKII) or KN-93 (0.1 μM, a CaMKII inhibitor) prevented IS-induced ionic current changes and arrhythmogenesis. In conclusion, IS modulates RVOT electrophysiology and arrhythmogenesis via enhanced CaMKII activity, which is attenuated by SN, leading to a novel therapeutic target for CKD arrhythmias.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"471-485"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Famciclovir Ameliorates Platelet Activation and Thrombosis by AhR-Regulated Autophagy.","authors":"Yue Ming, Qilong Zhou, Guang Xin, Zeliang Wei, Chengjie Ji, Kui Yu, Shiyi Li, Boli Zhang, Junhua Zhang, Youping Li, Hongchen He, Wen Huang","doi":"10.1007/s12012-025-09971-9","DOIUrl":"10.1007/s12012-025-09971-9","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) and their severe complications have posed immense challenges to global healthcare systems. A significant obstacle in this field lies in the development of innovative targets, mechanisms, and drugs to mitigate the side effects associated with current antiplatelet therapies. Through screening relevant CVD targets in the Gene Card database, we found that AhR appears to be linked to CVDs. Computer-aided drug screening and molecular docking techniques identified famciclovir as a potential AhR inhibitor. Further experiments demonstrated that famciclovir suppresses AhR expression and platelet activation in thrombin-stimulated platelets, significantly reducing mitochondrial damage and oxidative stress. Notably, oral administration of famciclovir significantly inhibits thrombin-induced platelet aggregation without affecting coagulation factors or thrombolysis systems. Moreover, famciclovir mitigates FeCl₃-induced carotid arterial thrombosis and cerebral thrombosis induced by middle cerebral artery occlusion. Our study suggests that inhibiting AhR expression with famciclovir effectively reduces platelet activation and thrombosis, offering promise as a potential therapeutic strategy for improving CVDs.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"486-497"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taxifolin Protects Against 5-Fluorouracil-Induced Cardiotoxicity in Mice Through Mitigating Oxidative Stress, Inflammation, and Apoptosis: Possible Involvement of Sirt1/Nrf2/HO-1 Signaling.","authors":"Mohammad H Abukhalil, Zina Al-Alami, Manal A Alfwuaires, Mohd Rasheeduddin Imran, Saleem H Aladaileh, Osama Y Althunibat","doi":"10.1007/s12012-025-09962-w","DOIUrl":"10.1007/s12012-025-09962-w","url":null,"abstract":"<p><p>Although 5-fluorouracil (5-FU) is widely utilized in cancer treatment, its side effects, including cardiotoxicity, limit its use. Taxifolin (TAX) is a bioactive anti-inflammatory and antioxidant flavonoid. This study aimed to elucidate the protective effect of TAX against 5-FU-induced cardiac injury in male mice. Mice were treated with TAX (25 and 50 mg/kg, orally) for 10 days and a single dose of 150 mg/kg 5-FU at day 8. Mice intoxicated with 5-FU showed increased creatine kinase-MB and lactate dehydrogenase activities and troponin I levels, with multiple cardiac histopathological changes. They also showed a significant increase in cardiac malondialdehyde (MDA) and nitric oxide (NO) and decreases in myocardial reduced glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.001). Pretreatment of 5-FU-injected mice with TAX suppressed cardiac injury, decreased MDA and NO contents (P < 0.001), and boosted antioxidant defenses in the myocardium. Moreover, TAX attenuated cardiac inflammatory response, as evidenced by the decreased expression levels of cardiac NF-κB p65, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines (P < 0.001). Largely, TAX ameliorated the decrease in Bcl-2 expression and the increase in BAX and caspase-3 in the heart. It also restored the cardiac Sirt1/Nrf2/HO-1 signaling pathway. In conclusion, TAX showed significant cardioprotective effects on 5-FU-induced cardiac injury and might represent a promising adjuvant in preventing cardiac injury associated with oxidative stress and inflammation.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"455-470"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLRC5 in Macrophages Promotes Atherosclerosis in Acute Coronary Syndrome by Regulating STAT3 Expression.","authors":"Jun Chen, Guoqin Chen, Jianhao Li, Dayu Wang, Weijie Liang, Shanjun Zhao","doi":"10.1007/s12012-024-09957-z","DOIUrl":"10.1007/s12012-024-09957-z","url":null,"abstract":"<p><p>The mortality rate of cardiovascular and cerebrovascular diseases ranks first among all causes. This study elucidated the role and potential mechanism of the NLRC5 gene in atherosclerosis (AS). We enrolled patients (number = 30) diagnosed with AS and healthy volunteers (number = 30) as controls from our hospital. In patients with AS, the levels of serum NLRC5 were up-regulated (Fig. 1A) and positively correlated with CIMT/CRP. In a mouse model of AS, the expression of serum NLRC5 mRNA was increased at 6 or 12 weeks after inducing AS. The expression of NLRC5 protein was found to be elevated in a mouse model of AS. The inhibition of NLRC5 reduced development of AS in ApoE^-/- Mice. Reducing NLRC5 inhibited the polarization of M2 macrophages and shifted macrophages towards proinflammatory M1 phenotype. STAT3 was identified as a target of NLRC5, with NLRC5 protein expression shown to reduce STAT3 ubiquitination. Methylation promoted NLRC5 DNA stability in vitro model of AS. Sh-NLRC5 increased M1/M2 macrophage ratio, foam cell formation and ox-LDL uptake. STAT3 reduced the effects of sh-NLRC5-mediated M1/M2 macrophage ratio in model of AS. These data confirmed that NLRC5 in macrophages promotes atherosclerosis in acute coronary syndrome by regulating STAT3 expression. This suggests that NLRC5 could be a potential target for the treatment of premature AS.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"365-378"},"PeriodicalIF":3.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}