Cardiovascular Toxicology最新文献

{"title":"Nanoparticle-Encapsulated 5-Azacytidine Attenuates Air Pollution-Induced Human Cardiac Fibroblast Activation.","authors":"Narainrit Karuna, Wan Wiriya, Kantaporn Kheawfu, Supachoke Mangmool, Chuda Chittasupho","doi":"10.1007/s12012-026-10161-4","DOIUrl":"10.1007/s12012-026-10161-4","url":null,"abstract":"<p><p>Quasi-ultrafine particles (qUFPs; particulate matter < 0.49 μm; PM_0.49) exposure is a key environmental contributor to cardiovascular disease, but its epigenetic impact on human cardiac fibroblasts (HCFs) remains unclear. Dysregulated DNMT activity and aberrant DNA methylation have been implicated in fibroblast activation and cardiac remodelling; however, the clinical utility of the DNMT inhibitor 5-Azacytidine (5-Aza) remains limited by chemical instability and toxicity, motivating nanoparticle (NP)-based delivery to improve stability and sustain therapeutic exposure. PM_0.49 was collected from Chiang Dao district, Chiang Mai Province, Thailand. HCFs were exposed to PM_0.49 (low and high concentrations), with or without pre-treatment using free 5-Aza or 5-Aza-loaded hyaluronic acid nanoparticles (5-Aza-NP). Epigenetic and pro-fibrotic gene markers were quantified using RT‑qPCR, and cell viability was assessed by MTT assay. Additionally, transcriptomic analysis using bulk RNA sequencing was performed to evaluate the effects of PM_0.49 on HCFs and their modulation by 5-Aza-NP treatment. HCFs exposed to high concentrations of PM_0.49 exhibited dysregulation of DNA methylation machinery, characterised by increased expression of DNMT1 and DNMT3A/B. Markers associated with fibroblast activation and pathogenic activation, including COL1A1 and α-SMA, were significantly induced following PM_0.49 exposure, whereas these alterations were attenuated following 5-Aza treatment. NP-based delivery of 5-Aza attenuated PM_0.49-induced HCF activation with reduced cytotoxicity under chronic exposure conditions. Bulk RNA sequencing identified transcriptomic alterations associated with PM_0.49 exposure that were partially modulated by 5-Aza-NP treatment, with selected findings validated by RT-qPCR. Exposure to a smoke haze-period PM_0.49 preparation from a biomass burning-affected rural site in Chiang Mai, Thailand, induced pathogenic HCF activation with molecular findings consistent with dysregulation of DNA methylation machinery. 5-Aza-NP attenuated PM_0.49-induced fibroblast activation and modulated associated transcriptomic alterations, suggesting a potential epigenetic-based therapeutic strategy against PM_0.49-induced cardiac fibroblast dysfunction. These findings warrant further validation across diverse PM compositions and sampling conditions.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469328","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":"Incretin-Based Therapies in Doxorubicin-Induced Cardiotoxicity: A Systematic Review of GLP-1 and Dual GIP/GLP-1 Agonists.","authors":"Seyedhesamoddin Khatami, Mohammadsadegh Faghihi, Ghazal Tavakoli, Sebastian Szmit, Mahmoud Yousefifard","doi":"10.1007/s12012-026-10119-6","DOIUrl":"10.1007/s12012-026-10119-6","url":null,"abstract":"<p><p>Doxorubicin (DOX)-induced cardiotoxicity remains a major limitation of cancer therapy. Incretin-based therapies are established cardiometabolic agents with pleiotropic cardiovascular effects; however, their potential role in mitigating DOX-related cardiac injury has not been systematically synthesized. We conducted a PRISMA 2020-compliant systematic review to evaluate the effects of incretin-based therapies on DOX-induced cardiotoxicity, with a focus on functional, structural, biomarker, and mechanistic outcomes. PubMed/MEDLINE, Embase, Web of Science, and Scopus were searched through 20 October 2025. Eligible studies included in vivo rodent models of DOX cardiotoxicity and any clinical studies directly evaluating incretin-based therapy during DOX exposure; in vitro studies, non-DOX models, combination-treatment studies, studies not focused on cardiotoxicity, gene therapy-based interventions, and reviews/editorials were excluded. Risk of bias and certainty of evidence were assessed using the SYRCLE tool and GRADE adapted for preclinical research. Thirteen rodent studies were included, and no eligible human study was identified. Investigated agents included liraglutide (n = 4), exenatide/exendin-4 (n = 4), semaglutide (n = 2), and tirzepatide (n = 3). In chronic cumulative-dose DOX models, incretin-based therapies were generally associated with preservation of left ventricular systolic function, with between-study improvements of approximately 7-20 percentage points in left ventricular ejection fraction, along with reductions in injury biomarkers. These effects were accompanied by attenuation of oxidative stress, inflammation, apoptosis, and, in some studies, ferroptosis. In contrast, findings were less consistent in acute single-dose models. Co-treatment during DOX exposure showed the most reproducible protective signal, whereas isolated pretreatment with liraglutide or tirzepatide and post-treatment with exenatide did not show a clear additional benefit. The evidence base is limited by exclusive reliance on small heterogeneous animal studies, predominantly male models, variable dosing/timing protocols, and low-to-very-low certainty of evidence. Overall, incretin-based therapies show biologically plausible cardioprotective effects in preclinical DOX cardiotoxicity, but these findings should be regarded as hypothesis-generating until confirmed in carefully designed clinical studies.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444340","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":"Associations Between Welding-Related Metals and Atherosclerotic Cardiovascular Disease Risk in Male Welders: The Mediating Role of Accelerated Biological Aging.","authors":"Yongbin Luo, Xiayun Dai, Zhenlong Chen, Jinfeng Jiang, Junpin Liu, Xiaolei Fu, Fan Wang, Xiaoliang Li","doi":"10.1007/s12012-026-10154-3","DOIUrl":"10.1007/s12012-026-10154-3","url":null,"abstract":"<p><p>The impact of metals on atherosclerotic cardiovascular disease (ASCVD) risk in workers occupationally exposed to welding fume remains unclear. We aimed to assess the associations between welding-related metals and 10-year ASCVD risk, and the mediating role of biological aging. Metals including chromium, manganese, nickel, lead, copper (Cu), and iron were detected and biological aging indices, including Klemera-Doubal method biological age (KDM-BA) and Phenotypic Age (PhenoAge), were calculated among 419 male welders in Wuhan, China. The participants had an average age of 42.77 years, of whom 93 (22.2%) fell into the high 10-year ASCVD risk group. Generalized linear models revealed that Cu was associated with elevated 10-year ASCVD risk [OR (95% CI) = 1.051 (1.017, 1.085), P = 0.003]. This association persisted even after adjustment for other metals. Moreover, we found positive associations between biological aging and 10-year ASCVD risk [KDM.Accel: OR (95%CI) = 1.170 (1.070-1.280); PhenoAge.Accel: OR (95% CI) = 1.122 (1.053-1.194)], as well as between Cu and biological aging [KDM.Accel: β (95% CI) = 1.888 (1.130-2.646); PhenoAge.Accel: β (95% CI) = 4.552 (3.406-5.698)]. Further analysis showed significant mediation roles of KDM.Accel and PhenoAge.Accel in the Cu-ASCVD association, with mediating proportions of 29.8% and 43.8%, respectively. We further constructed a lifestyle index, suggesting that a modifiable healthy lifestyle could decelerate aging and reduce the 10-year ASCVD risk. Our findings indicated that Cu was associated with increased ASCVD risk, and biological aging may mediate the Cu-ASCVD association. Adopting healthy lifestyles appears to mitigate biological aging, which is of great public health importance for preventing ASCVD.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444422","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":"Mechanisms of Cardiovascular Toxicity Induced by Silver Nanoparticles: A Systematic Review of Preclinical Evidence.","authors":"Muhammad Reva Aditya, Michael Owen Hogipranata, Vito Adriansyah, Athaya Rahmanardi Muhammad, Kameela Dilis Baheera, Artha Maressa Theodora Simanjuntak, Anna Fuji Rahimah, Putri Annisa Kamila, Hikmawan Wahyu Sulistomo","doi":"10.1007/s12012-026-10140-9","DOIUrl":"10.1007/s12012-026-10140-9","url":null,"abstract":"<p><p>Silver nanoparticles (AgNPs) have emerged as one of the most widely used nanomaterials in medical and consumer products, yet their cardiovascular safety remains inadequately characterized. While their antimicrobial properties are well-documented, accumulating evidence reveals that AgNPs pose a significant threat to the cardiovascular system. Exposure to AgNPs through inhalation, ingestion, or dermal contact enables these particles to enter systemic circulation, where they accumulate in cardiac and vascular tissues in a dose-, time-, and size-dependent manner. Once deposited, AgNPs initiate a cascade of pathological events, including oxidative stress, mitochondrial dysfunction, DNA damage, and disruption of calcium and sodium channel signaling. These molecular disturbances translate into physiological alterations such as bradycardia, atrioventricular conduction block, impaired contractility, and exacerbated ischemia-reperfusion injury. AgNPs also trigger endothelial activation, leading to upregulation of adhesion molecules, namely vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and recruitment of inflammatory cells, creating a proinflammatory and prothrombotic environment. Elevated cardiac biomarkers, including creatine kinase-MB fraction (CK-MB), brain natriuretic peptide (BNP), lactate dehydrogenase (LDH), and histopathological changes, including pericardial edema, myofibril disorganization, fibrosis, and inflammatory infiltration are consistently observed. Vascular dysfunction manifests as impaired vasorelaxation, enhanced vasoconstriction via endothelin-1 upregulation, thrombosis, and abnormal angiogenesis driven by vascular endothelial growth factor (VEGF) dysregulation. Although plant-based AgNPs have shown cardioprotective potential in limited studies, the overall evidence indicates significant cardiovascular risk. This systematic review synthesizes findings from 38 preclinical studies (35 in vivo, 3 in vitro), providing a comprehensive analysis of AgNP-induced cardiotoxicity with emphasis on oxidative stress, inflammation, and molecular dysregulation as core mechanistic drivers.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419092","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":"SETD2 Improves Endothelial Function and Angiogenesis in Diabetic Hindlimb Ischemia Via Activating ANGPT2-PI3K/AKT Pathway.","authors":"Langtao Wang, Qing Wang, Jiaxing Duan, Yu Tan, Yuanyuan Liu, Shuai Hu, Cheng Wang, Chen Yang, Yanzhu Long, Jinxuan Wang, Tao Yu, Tianhu Liu, Yaping Lan, Chaoping Yu, Liping Luo, Xiaozhen Dai","doi":"10.1007/s12012-026-10153-4","DOIUrl":"10.1007/s12012-026-10153-4","url":null,"abstract":"<p><p>Vascular endothelial dysfunction serves as a key pathological basis for diabetic vascular complications. Enhancing endothelial function and promoting angiogenesis are therefore critical strategies in the treatment of diabetic lower hindlimb ischemia (HLI). SETD2 is the primary methyltransferase for H3K36 trimethylation (H3K36me3) and is involved in vascular development, but its role in diabetes-associated endothelial dysfunction remains unknown. This study aimed to investigate the function and underlying mechanism of SETD2 in endothelial cells under diabetic conditions and in the context of diabetic HLI. A diabetic mouse model was established in endothelial-specific conditional SETD2 knockout (SETD2^ECKO) mice using a high-fat diet combined with streptozotocin (HFD/STZ) injection. After a single ligation of the common femoral artery in these mice, we observed that endothelial-specific conditional deletion of SETD2 significantly impaired blood flow recovery and reduced capillary density in the ischemic gastrocnemius muscle. In vitro, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose and palmitate (HG/PA) to simulate a diabetic microenvironment. It was found that HG/PA treatment down-regulated the expression of SETD2 and H3K36me3 in HUVECs. Functional studies revealed that SETD2 over-expression alleviated, whereas SETD2 inhibition aggravated, HG/PA-induced impairments in endothelial proliferation, migration, and tube formation. Mechanistically, SETD2 was found to positively regulate the expression of ANGPT2. KEGG enrichment analysis and Western blot validation indicated that SETD2 modulates the PI3K-AKT signaling pathway. Notably, exogenous ANGPT2 supplementation partially rescued endothelial dysfunction and restored AKT phosphorylation in SETD2-inhibited cells under HG/PA conditions. In conclusion, SETD2 preserves endothelial function and promotes angiogenesis by up-regulating ANGPT2 and subsequently activating the PI3K-AKT signaling axis. The SETD2-ANGPT2-PI3K/AKT pathway may represent a promising therapeutic target for the treatment of diabetic vascular complications.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419052","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":"Molecular Mechanisms of Effects of Lead and Cadmium Co-exposure on Atrial and Ventricular Myocardium: Soluble Salts Versus Nanoparticles.","authors":"Oksana Gerzen, Veronika Votinova, Salavat Nabiev, Alyona Tzybina, Natalia Stukalova, Maria Zhigulina, Svetlana Klinova, Ilzira Minigalieva, Marina Sutunkova, Larisa Nikitina","doi":"10.1007/s12012-026-10152-5","DOIUrl":"10.1007/s12012-026-10152-5","url":null,"abstract":"<p><p>Lead (Pb) and cadmium (Cd) are ubiquitous xenobiotics associated with cardiovascular diseases. While Pb and Cd cardiotoxicity is well studied, the molecular mechanisms of their co-exposure are poorly understood. We aimed to investigate the cardiotoxic effects of subchronic co-exposure to soluble versus nanoparticle forms of Pb and Cd on the atrial and ventricular myocardium. Rats received 18 intraperitoneal injections of combined Pb(C₂H₃O₂)₂ (6.01 mg/kg b.w.) and CdCl₂ (0.377 mg/kg b.w.) solution over 6 weeks (Pb+Cd group). Another group received 18 injections of combined PbO (2.32 mg/kg b.w.) and CdO (0.22 mg/kg b.w.) nanoparticle (NP) suspension (Pb_NP+Cd_NP group) over 6 weeks. We examined the relative force, sliding velocity of actin and regulated thin filaments over myosin, the fraction of motile filaments, and the characteristics of the \"pCa-velocity\" and \"pCa-fraction of motile filaments\" relationships using an in vitro motility assay. We analyzed myosin heavy (MHC) and light (MLC) chains' isoform composition and regulatory light chain (MLC2) phosphorylation by SDS-PAGE. In the Pb+Cd group, atrial and left-ventricular (LV) myosin kinetics was reduced but right-ventricular (RV) myosin kinetics was increased. The MHC ratio shifted toward α-MHC in the RV and toward β-MHC in the LV, and MLC2 phosphorylation in the atria was increased. In the Pb_NP+Cd_NP group, myosin kinetics was reduced in all heart chambers, and the MHC ratio shifted toward the β-isoform in the ventricles. The effects of co-exposure to Pb and Cd differ from those of isolated exposures and depend on the chemical forms of the toxicants and the specific heart chamber.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419082","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 Neuroimmune Mechanisms Linking Smoking and Infection to Atherosclerosis: Chronic vs. Surge.","authors":"Paulo Roberto Benchimol-Barbosa","doi":"10.1007/s12012-026-10155-2","DOIUrl":"10.1007/s12012-026-10155-2","url":null,"abstract":"<p><p>The pathogenesis of atherosclerosis has progressively shifted from a lipid-centric model to one that recognizes inflammation as the central driver. Smoking is a well-established chronic risk factor, whereas acute infections are increasingly recognized as transient triggers of acute cardiovascular events. This review synthesizes the distinct yet overlapping mechanisms by which chronic smoking and acute infections contribute to atherogenesis and plaque destabilization within an integrated neuroimmune framework. This narrative review was developed using AI-assisted literature search tools (ChatGPT, OpenAI; Claude, Anthropic) to identify relevant publications from 1990 to 2025. All references were independently verified using PubMed and original source links. Selection prioritized mechanistic studies addressing inflammatory pathways, endothelial dysfunction, and immune modulation. Smoking promotes atherogenesis through sustained endothelial injury, lipoprotein oxidation, chronic sympathetic activation, and hematopoietic reprogramming, favoring proinflammatory monocyte mobilization. Infections elicit acute cytokine surges, sympathetic-mediated macrophage activation, and prothrombotic cascades that destabilize preexisting plaques. Smoking contributes to plaque initiation and growth, whereas infections primarily act as event triggers. Atherosclerosis emerges from chronic and episodic inflammatory processes with distinct temporal profiles. Smoking is a continuous driver of plaque formation, whereas acute infections promote plaque destabilization. Future research should examine their interplay, particularly in smokers exposed to recurrent or low-grade infectious states.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419102","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":"The mtROS-Mitophagy Axis: A Decisive Redox Hub Governing Cell Fate in Myocardial Ischemia-Reperfusion Injury.","authors":"Wei Wang, Zhihao Xu, Wei Liu, Yaolu Kang, Fan Zhang, Qing Yu, Ronglin Cai","doi":"10.1007/s12012-026-10137-4","DOIUrl":"10.1007/s12012-026-10137-4","url":null,"abstract":"<p><p>The progression of myocardial ischemia-reperfusion injury (MIRI) is orchestrated by a decisive, bidirectional dialogue between mitochondrial reactive oxygen species (mtROS) and mitophagy. This review advances the concept of a dynamic \"mtROS-mitophagy axis\" as the central redox hub determining cardiomyocyte fate. We systematically dissect how moderate mtROS initiates protective mitophagy via key pathways (e.g., PINK1/Parkin, FUNDC1) and reinforces endogenous defenses through the Sirt3-FoxO3a integrator. Conversely, an mtROS burst disrupts this axis, triggering a vicious cycle of oxidative damage, impaired autophagic flux, and Drp1-mediated pathological fission. Critically, we emphasize the double-edged and temporally governed nature of this axis, arguing that its precise spatiotemporal modulation represents the next frontier in cardioprotection. Beyond mechanism, this synthesis provides a unified framework for developing novel therapies and for evaluating the cardiac safety of pharmacological agents, directly aligning with the core pursuits of cardiovascular redox biology and toxicology.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419047","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":"E-cigarette Aerosol Containing Nicotine Increases Aortic Stiffness in Young Mice.","authors":"Pireyatharsheny Mulorz, Joscha Mulorz, Agnesa Mazrekaj, Hsiang-Han Liu, Wiebke Ibing, Joshua M Spin, Lasse Bach Steffensen, Hans C Beck, Uwe Raaz, Kensuke Toyama, Hubert Schelzig, Philip S Tsao, Markus U Wagenhäuser","doi":"10.1007/s12012-026-10156-1","DOIUrl":"10.1007/s12012-026-10156-1","url":null,"abstract":"<p><p>E-cigarettes (E-cigs) are widely used especially among young people, but the effects on vascular stiffening and remodeling are poorly understood. This study evaluates the effects of short-term e-cig exposure on young vs. adult mice and the effects of e-cig derived chemicals present in plasma and urine of exposed animals on cultured endothelial cells (EC) and vascular smooth muscle cells (SMC). C57BL/6J mice of 6- and 14-weeks of age were exposed to unflavored e-cig aerosol with and without nicotine (50% propylene glycol, 50% vegetable glycerol +/- 24 mg/ml nicotine 3 weeks, puff duration of 9 s per minute, for 60 min/day) and aortic tissue subjected to in- and ex-vivo assessment of stiffness and histological evaluation. Major chemical constituents of e-cig aerosol were analyzed in plasma and urine samples, and cultured human aortic ECs and SMCs were treated with these chemicals, including acrolein, formaldehyde and nicotine. Changes in gene and protein expression were quantified, and functional ROS and MMP assays were performed. Pulse wave velocity revealed increased stiffness upon treatment with e-cig aerosol, and to a greater extent with the inclusion of nicotine (114% in 6-week-old and 112% in 14-week-old mice vs. baseline, p < 0.001), which was also observed in ex-vivo myography in aortic infrarenal and thoracic segments in 6-week-old mice after e-cig exposure. Aortic elastin content in these mice was decreased when compared to room-air controls (-24% in 6-week-old and - 36% in 14-week-old mice in thoracic aorta, p < 0.05). In vitro treatment with some of the different chemical compounds present in e-cig aerosol led to an increase in endothelial activation markers, and extracellular remodeling proteins. Wire myography showed an endothelium-independent decrease in relaxation in young murine aortas treated with nicotine. Our results indicate that short-term exposure over three weeks to e-cig aerosol leads to marked changes in murine aortic stiffness and vascular remodeling, potentially predisposing for cardiovascular disease conditions despite the superior remodeling capabilities of young animals.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403688","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":"Calcium and TRPML-Mediated Autophagy: Implications in Cancer, Cardiovascular Diseases, and Cardio-Oncology.","authors":"Joseph Adu-Amankwaah, Vincent Kawuribi, Manuella Quaye, Ling Sha, Siwen Fan, Prakriti Kaur, Vishal Sharma, Osinachi Uchechi Okpoko, Zeyuan Yin","doi":"10.1007/s12012-026-10159-y","DOIUrl":"10.1007/s12012-026-10159-y","url":null,"abstract":"<p><p>Autophagy is an essential cellular process that maintains homeostasis, regulates organelle turnover, preserves energy balance, and ensures protein quality control. Central to autophagy regulation is calcium (Ca²⁺) signaling, which integrates inputs from multiple Ca²⁺ channels and handling proteins, including L-type and T-type voltage-gated Ca²⁺ channels, transient receptor potential mucolipin (TRPML) channels, inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), the mitochondrial calcium uniporter (MCU), sodium-calcium exchangers (NCX), sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and calcium/calmodulin-dependent protein kinase II (CaMKII). Although these regulators are well studied, their disease-specific functions remain context-dependent and complex. In cancer, Ca²⁺-regulated autophagy enhances metabolic flexibility, maintains mitochondrial integrity, promotes resistance to chemotherapy, and facilitates immune evasion, thereby supporting tumor growth and survival. Conversely, in cardiovascular diseases (CVDs), autophagy enables cardiomyocytes to adapt to ischemic, inflammatory, and hemodynamic stress. However, dysregulated Ca²⁺ signaling and impaired autophagic flux contribute to tumor progression and pathological cardiac remodeling, respectively. This review explores the molecular mechanisms underlying Ca²⁺-dependent autophagy in cancer and CVDs, providing a detailed analysis of shared signaling pathways and potential therapeutic targets. Discussed in this review, the emerging field of cardio-oncology highlights a mechanistic convergence in which anticancer therapies disrupt cardiomyocyte Ca²⁺ homeostasis, causing mitochondrial Ca²⁺ overload, ER stress, and defective autophagy, ultimately leading to cardiotoxicity, while tumor cells exploit the same pathways to survive therapeutic stress. By elucidating the spatiotemporal dynamics of Ca²⁺ signaling and autophagy, we identify common molecular hubs and propose precision strategies to enhance anticancer efficacy while preserving cardiac function, advancing translational innovation in cardio-oncology.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403709","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}