Cardiovascular Toxicology最新文献

{"title":"Arrhythmia Inducibility in the CAVB Dog Model, A Critical Analysis on Underlying Factors.","authors":"Joanne J A van Bavel, Henriëtte D M Beekman, Marien J C Houtman, Marc A Vos, Marcel A G van der Heyden","doi":"10.1007/s12012-025-10033-3","DOIUrl":"10.1007/s12012-025-10033-3","url":null,"abstract":"<p><p>The dog with chronic atrioventricular block (CAVB) combines a number of risk factors associated with Torsade de Pointes (TdP) arrhythmias. Nevertheless, approximately 33% of the animals are resistant to dofetilide-induced TdP arrhythmia. Of a group of 78 experimentally identical CAVB dogs, we compared TdP inducible vs. non-inducible animals for a set of basic, and cardiac electrical and mechanical parameters. Body weight, but not sex or age, is associated with TdP inducibility. Of the cardiac parameters, longer ventricular repolarization duration and increased contractility at baseline are associated with dofetilide-induced TdP arrhythmias. Differences in cardiac parameters disappeared upon dofetilide infusion. We discuss that prolonged repolarization and increased contractility may be early indications of calcium-mediated early after depolarization that may develop into TdP arrhythmias.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1344-1351"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473997","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":"Inhibition of USP5 Attenuates Atherosclerosis by Suppressing PDCD4-Mediated Endothelial Dysfunction: Evidence from In Vitro HUVEC and In Vivo Models.","authors":"Yali Chen, Yihuan Wang, Tingting Wu, Xiaolei Guo, Xueyang Bai, Lirui Wang, Peipei Yan, Zhe Zheng, Lili Xiao, Ling Li","doi":"10.1007/s12012-025-10007-5","DOIUrl":"10.1007/s12012-025-10007-5","url":null,"abstract":"<p><p>Atherosclerosis (AS) is a fundamental pathological process underlying cardiovascular disease (CVD), which begins with dysfunction in the endothelial system resulting from damage to vascular endothelial cells. Our research demonstrates that the deubiquitinating enzyme USP5 is upregulated in endothelial cells of AS plaques. In vitro, USP5 knockdown enhanced cell viability, whereas attenuated ox-LDL-induced apoptosis, oxidative stress, inflammation, and endothelial dysfunction in HUVECs. In vivo studies in a mouse model of atherosclerosis showed that USP5 inhibition significantly reduced plaque formation, collagen deposition, and inflammatory cell infiltration. Protein mass spectrometry analysis and immunoprecipitation assays show that USP5 interacts with programmed cell death 4 (PDCD4). PDCD4 overexpression rescues USP5 knockdown effects on HUVECs exposed to ox-LDL. This study elucidates the biological functions of the USP5/PDCD4 axis in the injury of cells of the vascular endothelium during AS and suggests that targeting this axis could offer a potential therapeutic strategy for atherosclerosis.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1272-1287"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494745","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":"Statins: Novel Approaches for the Management of Doxorubicin-Induced Cardiotoxicity-A Literature Review.","authors":"Seyed Saeed TamehriZadeh, Mahla Khalaji, Mobina Tajdari, Helia Mavaddat, Sebastian Szmit, Naser-Aldin Lashgari, Nazanin Momeni Roudsari, Hamed Abbasi-Kashkoli, Maciej Banach, Amir Hossein Abdolghaffari","doi":"10.1007/s12012-025-10030-6","DOIUrl":"10.1007/s12012-025-10030-6","url":null,"abstract":"<p><p>This study aims to evaluate the potential role of statins in preventing doxorubicin-induced cardiotoxicity. With the rising number of cancer survivors and the persistent use of doxorubicin in treatment protocols, there is an urgent need for effective cardioprotective strategies to mitigate long-term cardiovascular complications. Statins, widely used for cardiovascular disease prevention, offer a promising repurposing opportunity due to their pleiotropic effects. A comprehensive review of existing animal and clinical studies was conducted to assess the cardioprotective effects of statins. Key mechanisms such as reduction of oxidative stress, inflammation, and apoptosis were examined, alongside current clinical evidence evaluating their use in patients receiving doxorubicin. Preclinical studies consistently demonstrate that statins significantly reduce doxorubicin-induced cardiotoxicity by modulating multiple cellular pathways involved in oxidative stress, inflammation, and programmed cell death. These findings highlight statins' multifaceted mechanisms of action in protecting cardiac tissue. Numerous observational studies have shown that statin therapy may reduce the incidence and severity of doxorubicin-induced cardiotoxicity, reflected by less decline in left ventricular ejection fraction and a lower risk of heart failure in those receiving statins, but results from randomized controlled trials remain inconsistent. Given the growing burden of cancer therapy-related cardiovascular disease and the established safety profile of statins, further large-scale clinical trials are warranted to confirm their protective role, determine optimal dosing strategies, and facilitate integration into oncology practice. Establishing their utility could improve long-term outcomes for cancer patients vulnerable to cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1429-1452"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599532","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":"Chronic Anatabine Administration Attenuates Cardiovascular Activity by Targeting NF-κB/NLRP3/Caspase-1-Dependent Pyroptosis and Oxidative Stress in Paraventricular Nucleus of Hypertensive Rat.","authors":"Qing Su, Shao-Jun Li, Jun-Yu Zhou, Jin-Bao Yang, Fang Zhao, Guo-Quan Zou, Jia-Xuan Ma, Qi Liu, Yuan-Yuan Feng, Cui-Ling Yang, Ying Li, Hong-Bao Li, Meng-Lu Xu","doi":"10.1007/s12012-025-10034-2","DOIUrl":"10.1007/s12012-025-10034-2","url":null,"abstract":"<p><p>Hypertension is characterized by chronic inflammation. Anatabine, a natural alkaloid with anti-inflammatory properties, has demonstrated potential in regulating inflammatory pathways. However, its impact on cardiovascular activity in the context of hypertension remains unclear. The aim of this study was to explore the effects of anatabine on cardiovascular activity in hypertensive rats, with a specific focus on the underlying mechanisms related to inflammation and oxidative stress, particularly the role of NLRP3 inflammasome and pyroptosis in the PVN. Fecal samples were collected from male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, followed by untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS). Anatabine (ANT) was identified as enriched in WKY while lacking in SHR and thus was subcutaneously administered via mini-pump (0.014 mg/kg/min) in SHR or WKY rats for 12 weeks. Systolic blood pressure was recorded weekly. In vitro, microglia (HMC3) were divided into control, angiotensin II (Ang II), Ang II + anatabine, and Ang II + anatabine + PapRIV (Pap, NF-κB activator) groups. High blood pressure significantly triggered nucleotide-binding domain, leucine-rich-containing family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation (ASC, Caspase-1, and NLRP3), and pyroptosis (GSDMD) in the hypothalamic paraventricular nucleus (PVN), which evoked massive inflammatory cytokine production (IL-1β, TNF-α, IL-18, and MCP-1) and oxidative stress responses (Cu/Zn-SOD activity, GSH-PX, and MDA) in the SHR group. Notably, anatabine not only prevented cardiac structural remodeling and attenuated sympathetic activation but also reduced the inflammatory reaction from the NF-κB activity, NLRP3-dependent inflammasome and pyroptosis, and decreased reactive oxygen species (ROS) overproduction in the PVN of hypertensive rats. In vitro, microglia stimulated inflammation after adding Ang II; oxidative stress responses were activated, while the inflammasome compounds and cytokines were overexpressed. The anatabine inhibited NF-κB activity, NLRP3/caspase-1-dependent pyroptosis and oxidative stress in Ang II-induced microglia. Conversely, those responses were aggravated after the NF-κB activator in HMC3. Chronic hypertension activates the NLRP3 inflammasome and pyroptosis-driven inflammatory responses, leading to oxidative stress in the PVN. Sustained administration of anatabine reached the PVN and suppressed the NF-κB/NLRP3/caspase-1-dependent pyroptosis pathway in microglia, reducing excessive ROS generation in the PVN, thereby effectively reducing sympathetic drive, attenuating blood pressure, and preventing cardiac structural remodeling in the process of hypertension. These findings suggest anatabine as a promising therapeutic agent for managing hypertension-related chronic inflammation.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1352-1368"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673981","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":"Atherosclerotic Cardiovascular Disease in Gulf War Veterans in Relation to Deployment Exposures.","authors":"Sarah T Ahmed, Ruosha Li, Lea Steele, Peter Richardson, Kellie Sims, Rachel Quaden, Kelly M Harrington, Vijay Nambi, John M Gaziano, Robert Morgan, George L Delclos, Drew A Helmer","doi":"10.1007/s12012-025-10013-7","DOIUrl":"10.1007/s12012-025-10013-7","url":null,"abstract":"<p><p>Many 1990-1991 Gulf War Veterans (GWVs) were exposed to toxicants and environmental hazards during deployment, including oil well fire smoke, chemical/biological agents, pyridostigmine bromide (PB) pills, and pesticides. Multiple constituents of smoke are associated with increased risk for atherosclerotic cardiovascular diseases (ASCVD), and other toxic exposures have been associated with autonomic and lipid dysfunction. We used data from the Gulf War Era Cohort and Biorepository Study of veterans deployed to Gulf War in 1990-1991 (n = 942). We evaluated the association of deployment exposures (no, yes (1-6 days), (7-30 days), (31 + days), and not sure) with clinical risk factors (hypertension, diabetes, high cholesterol) and ASCVD using multivariable logistic regression. We adjusted for all clinical risk factors in the models to test the association of military exposures and ASCVD. We found that 7-30 days exposure to oil well fire smoke (OR: 2.95, CI: 1.40, 6.19), PB pills (OR: 2.37, CI: 1.06, 5.32), and chemical/biological agents (OR: 3.60, CI: 1.04, 12.51) were associated with ASCVD. Exposure to chemical/biological agents for 7-30 days was also associated with hypertension (OR: 4.18, CI: 1.48, 11.86) and for 31 + days was associated with ASCVD (OR: 4.24, CI:1.20, 14.94). The associations between oil well fire smoke and chemical/biological agents with ASCVD remained significant in models adjusting for clinical risk factors. For GWVs, exposure to oil well fire smoke, chemical/biological agents, and PB pills were associated with ASCVD. These exposures may represent population-specific risk enhancers for ASCVD and may be considered in individualized clinical risk assessment.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1263-1271"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567140","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":"The Cardiovascular Burden of Gonadotropin-Releasing Hormone (GnRH) Therapy: Mechanisms, Risks, and Interventions.","authors":"Sepideh Miraj, Amir Mohammad Karimi Forood, Shideh Azimi, Paria Panahinia, Erfaneh Ebadi, Somayeh Moradpanah, Mehrnaz Nayebzadeh, Atoosa Etezadi","doi":"10.1007/s12012-025-10025-3","DOIUrl":"10.1007/s12012-025-10025-3","url":null,"abstract":"<p><p>Gonadotropin-releasing hormone (GnRH) therapy, a cornerstone in the treatment of various oncological and reproductive conditions, has been increasingly associated with significant cardiovascular risks, particularly when administered long-term. This review examines the complex relationship between GnRH therapy, metabolic dysregulation, and cardiotoxicity, with a focus on the mechanisms driving these cardiovascular outcomes. Prolonged GnRH suppression induces a spectrum of metabolic disturbances, including insulin resistance, dyslipidemia, and obesity, all of which elevate the risk of cardiovascular events such as hypertension, myocardial infarction, and stroke. These risks are further influenced by sex-specific differences and pre-existing cardiovascular conditions, necessitating tailored therapeutic strategies. The review highlights the urgent need for comprehensive monitoring and early intervention in patients undergoing GnRH treatment, with a particular emphasis on personalized care approaches. Additionally, we explore both pharmacological and non-pharmacological interventions aimed at mitigating these risks, including the potential of next-generation GnRH modulators and combination therapies. The need for future research is underscored, particularly in understanding the molecular and cellular mechanisms underlying cardiovascular toxicity, identifying predictive biomarkers, and developing safer therapeutic alternatives. This review provides a comprehensive framework for clinicians and researchers working to optimize the benefits of GnRH therapy while minimizing its cardiovascular burden, ultimately improving patient outcomes across various clinical settings.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1411-1428"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583192","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":"Safety of Permissive Cardiotoxicity of Trastuzumab in Patients with Breast Cancer: A Systematic Review and Meta-Analysis.","authors":"Amira Mohamed Taha, Ramez M Odat, Wesam Abd El-Tawab Moawad, Sara Adel Abdelkader Saed, Basma Ehab Amer, Dang Nguyen, Dalal Salama Salem, Linh Tran, Loay Kassem","doi":"10.1007/s12012-025-10037-z","DOIUrl":"10.1007/s12012-025-10037-z","url":null,"abstract":"<p><p>Cardiotoxicity is a recognized adverse effect associated with anti-HER2 therapies. The Trastuzumab-mediated cardiac dysfunction is not dose-dependent and lacks ultrastructural changes, allowing potential recovery after a few months. There is no consensus on the management of patients who develop cardiotoxicity. This meta-analysis aims to assess the safety of the permissive cardiotoxicity of Trastuzumab in patients with breast cancer. We searched PubMed, Cochrane Library, and Embase up to October 2023 for retrospective or prospective studies that investigated the safety of Trastuzumab in patients with breast cancer who continued Trastuzumab therapy after asymptomatic ejection fraction (EF) decline. We conducted a pooled meta-analysis for the subsequent cardiac events, cardiac mortality, and all-cause mortality. We assessed the quality of included studies using the Newcastle-Ottawa Scale and ROBIN-1 tool. A total of eight cohort studies (six retrospective and two prospective), comprising 222 patients, were found eligible and were included in our analysis. The pooled incidence of cardiac events, cardiac-related mortality, and all-cause mortality was 18% (95% CI 13% to 24%), 5% (95% CI 2% to 10%), and 8% (95% CI 2% to 28%), respectively. The incidence of symptomatic or severe cardiac events was lower in those who received cardioprotective medications concomitant with Trastuzumab. Most patients received either angiotensin-converting-enzyme inhibitors, beta-blockers, or a combination of both. Continuation of planned Trastuzumab therapy with concomitant use of cardioprotective medications can be a safe and effective approach for breast cancer control in patients with asymptomatic EF decline.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1369-1380"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583099","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":"Epigenetic Alterations Induced by Air Pollution: A Key Driver in Atherosclerosis Development.","authors":"Pouya Goleij, Mohammad Amin Khazeei Tabari, Pantea Majma Sanaye, Ali Moradi, Hossein Karimi, Aryan Rezaee, Alan Prem Kumar, Haroon Khan","doi":"10.1007/s12012-025-10036-0","DOIUrl":"10.1007/s12012-025-10036-0","url":null,"abstract":"<p><p>Air pollution, a global health concern, is linked to atherosclerosis through epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNA regulation. Long-term exposure to air pollution such as particulate matter 2.5 (PM 2.5), polycyclic aromatic hydrocarbons (PAHs), and heavy metals can induce alterations in DNA methylation patterns, especially in genes regulating inflammation and cholesterol metabolism, contributing to atherosclerosis development. DNA methylation plays a fundamental role in regulating gene expression by silencing or activating genes involved in endothelial dysfunction, inflammation, and lipid metabolism, all of which contribute to atherosclerosis progression. Moreover, it explores the influence of air pollution on histone modifications, emphasizing their role in pathways critical to atherosclerotic progression. Histone modifications, such as acetylation and methylation, alter chromatin structure and gene accessibility, impacting key signaling pathways related to vascular inflammation and plaque formation. It explores the interconnection between air pollution and non-coding RNA (ncRNA) modifications, shedding light on the significance of miRNAs and lncRNAs as potential biomarkers indicative of cardiovascular susceptibility triggered by exposure to particulate matter (PM). Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), modulate post-transcriptional gene regulation, influencing inflammatory responses, oxidative stress, and endothelial function in atherosclerosis. Understanding these epigenetic changes is vital for developing strategies to mitigate air pollution's impact on cardiovascular health.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1288-1303"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559302","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":"MLN4924, A Neddylation Inhibitor, Improves the Vascular Reactivity but Causes Early Mortality in Polymicrobial Sepsis: Effect on Vascular RhoA/ROCK Signaling.","authors":"Divyanshi Gupta, Raut Akash, S Simran Kour, Ballabh Dangra, Sonam Kumari, Himani Pandey, Soumen Choudhury, Amit Shukla, Neeraj K Gangwar, Shyama N Prabhu","doi":"10.1007/s12012-025-10039-x","DOIUrl":"10.1007/s12012-025-10039-x","url":null,"abstract":"<p><p>Vascular hyporeactivity is one of the the leading causes of death in sepsis. Ubiquitylation regulates the turnover of different cellular proteins; however, its role in controlling vascular dysfunction in sepsis is largely unknown. Herein, we aimed to evaluate the role of Cullin-3-RING ubiquitin ligase in regulating vascular contractile protein (RhoA) homeostasis and thereby regulating sepsis-induced vascular dysfunction. Sepsis was induced by caecal ligation and puncture (CLP) in mice. Cullin neddylation inhibitor (MLN4924) was evaluated for its possible therapeutic use in experimental sepsis in mice. Sepsis significantly impaired vascular RhoA/ROCK signaling as corroborated by marked increase in vasorelaxant response to Y-27632 (a Rho kinase inhibitor) which was found to be mediated by iNOS/NO/sGC pathway. Further, a significant down-expression of vascular RhoA/ROCK in septic mice was accompanied with increase in the protein expression of neddylated cullin3. Additionally, the silencing of cullin3 in vascular smooth muscle cells resulted in increase in the protein expression of RhoA. Treatment of septic mice with MLN4924, a neddylation inhibitor, significantly improved the vascular reactivity as evidenced by reduction in relaxant response to Y-27632, increase in protein level of RhoA in aorta with concomitant restoration of the contractile response to nor-adrenaline. However, MLN4924 treated mice showed higher bacterial load in blood, peritoneal lavage, lungs and spleen of septic mice. Taken together, sepsis-induced increase in cullin3 mediated degradation of RhoA possibly contributes to the vascular hyporeactivity. Thus, inhibition of vasculo-specific cullin neddylation by MLN4924 seems a potential therapeutic target for treating sepsis-induced vascular dysfunctions.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1304-1320"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590546","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":"Empagliflozin Promotes Revascularization in Diabetic Mice Hindlimb Ischemia by Improving Vascular Endothelial Cell Function.","authors":"Hanjie Liu, Yingfan Li, Xiaoqi Zhou, Ting Chen, Yuanyuan Liu, Shuai Hu, Cheng Wang, Qing Wang, Jianxiong Xu, Xiangyu Zhou, Yang Shen, Chaoping Yu, Tianhu Liu, Jinxuan Wang, Xiaozhen Dai","doi":"10.1007/s12012-025-10035-1","DOIUrl":"10.1007/s12012-025-10035-1","url":null,"abstract":"<p><p>Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, offers vascular protection beyond its glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). As endothelial dysfunction is a key initiator of vascular disease, understanding the precise regulatory mechanisms of EMPA in diabetic vascular complications is of great interest. In this study, we evaluated the therapeutic potential of EMPA in promoting blood flow recovery and revascularization under diabetic conditions using a hindlimb ischemia (HLI) model in db/db mice. We also investigated the effects of EMPA on the angiogenic function of endothelial cells exposed to high glucose and palmitate (HG/PA) conditions, mimicking the metabolic milieu of T2DM. The results demonstrated that EMPA significantly improved blood perfusion recovery in ischemic limbs, concomitant with enhanced angiogenesis and arteriogenesis in the ischemic gastrocnemius muscle. At the cellular level, EMPA effectively preserved endothelial function by mitigating HG/PA-induced impairments in cell migration and tube formation. Notably, EMPA treatment substantially ameliorated diabetes-induced oxidative stress in both muscle tissues and endothelial cells. Mechanistic studies revealed that EMPA upregulated antioxidant gene expression through SETD2-mediated pathways, thereby restoring endothelial angiogenic function under diabetic conditions. Taken together, these findings highlight that EMPA's therapeutic potential in diabetic HLI by attenuating oxidative stress and enhancing endothelial function.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":" ","pages":"1331-1343"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483225","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}