Cardiovascular Toxicology最新文献

Ventricular aneurysm is a serious complication following myocardial infarction. Increasing evidence suggests that exercise-based cardiac rehabilitation plays a protective role in cardiovascular disease. However, the effects of exercise on ventricular aneurysm and the underlying mechanisms remain poorly understood. Therefore, this study aimed to establish a murine model of ventricular aneurysm and investigate the impact of exercise on this condition, along with its potential mechanisms. In this study, using proximal coronary artery ligation, a murine cardiac ventricular aneurysm model was established and evaluated by real-time myocardial contrast echocardiography. Wild-type male C57BL/6 mice with ventricular aneurysms were randomly assigned to three groups: a Sedentary group (no exercise, n = 7), a moderate-intensity exercise group (5 m/min adaptive exercise for 2 weeks, followed by 12-m/min moderate-intensity exercise for 8 weeks, n = 9), and a high-intensity exercise group (5-m/min adaptive exercise for 2 weeks, followed by 18-m/min high-intensity exercise for 8 weeks, n = 7). After 8 weeks of exercise intervention, moderate-intensity exercise was found to significantly enhance cardiac function, reduce myocardial fibrosis, and inhibit fibroblast activation. In contrast, high-intensity exercise resulted in deteriorated cardiac function and aggravated cardiac injury. Mechanistically, this paradoxical effect was linked to the regulation of PTEN stability and subsequent modulation of Smad2/3 signaling pathway. This study provides a theoretical foundation for the role of exercise in managing ventricular aneurysms and offers insights into optimal exercise intensity levels.

Titanium dioxide (E171) is utilized in the food industry more frequently than other food additives because of its superior properties as a white colorant. Numerous in vitro studies have shown that E171 exhibits toxic effects on various cell types after a limited period of exposure. Previous observations indicate that E171 penetrates the cytoplasm of rat heart H9c2 myoblasts, leading to cell destruction after two days of treatment and impairing cardiac performance ex vivo within 10 min. Humans consume products containing E171 for extended periods; therefore, H9c2 cells were exposed to E171 once (short exposure) or multiple times (long exposure), and its toxic effects were examined after 5 weeks. Transmission electron microscopy (TEM) was used to analyze morphology and internalization. Cell counts were assessed, and cell death was evaluated using annexin plus propidium iodide (PI) and TUNEL assay. On the other hand, rats were orally administered E171 either once (acute exposure) or multiple times every other day over three months (chronic exposure), and the heart biomechanics were evaluated in a Langendorff system, as well as the infarct size by triphenyltetrazolium chloride staining. Experiments on H9c2 cells indicated that a single exposure to E171 (short) induced its absorption, a decrease in the cell number, and death after one week of exposure, and all these events were reversed after 5 weeks. Long exposure to E171 led to its internalization, inhibition of cell proliferation, alterations in cell morphology, and increased mortality during all weeks of treatment. Acute administration of E171 to rats did not induce alterations in cardiac function; however, chronic administration led to dysfunction, as indicated by a reduction in pressure and contractility index. The findings indicate that H9c2 cells and rodent hearts can recover after a brief E171 exposure, while prolonged exposure leads to substantial toxicity in both cardiac cells and cardiac tissue. Therefore, prolonged exposure to E171 could be potentially toxic to humans and lead to the development of cardiac dysfunctions.

Nanoparticle (NP) exposure has been implicated in accelerating atherosclerosis, while phytochemicals like epigallocatechin gallate (EGCG) may counteract these effects through metabolic modulation. This study investigates whether EGCG mitigates SiO₂ NP-induced foam cell formation in atherosclerotic mice by restoring metabolic homeostasis. ApoE-/- mice were administered 1600 mg/kg SiO₂ NPs, 80 mg/kg EGCG, or both, via daily intragastric gavage for totally 28 days. Although SiO₂ NPs did not significantly alter cardiac contractile function or increase Oil Red O-positive areas in entire aortas, they markedly elevated BODIPY 493/503-positive lipid accumulation in the aortic sinus, whereas co-treatment with EGCG completely abrogated this effect. Metabolomic profiling revealed distinct perturbations induced by SiO₂ NPs versus SiO₂ NPs + EGCG. SiO₂ NPs up-regulated amino acids (L-norvaline, leucine, N-acetylalanine) and fatty acids (decanoic acid, trans-vaccenic acid, octanoic acid) but down-regulated nucleotides (cAMP, adenine, AMP), while EGCG co-exposure reversed these changes. Pathway enrichment analysis indicated that SiO₂ NPs + EGCG co-exposure more profoundly affected porphyrin metabolism (map00860) and fatty acid biosynthesis (map00061) compared to SiO₂ NPs alone. Western blotting demonstrated SiO₂ NP-induced activation of autophagy (increased LC3-II/I ratio) and apoptosis (increased pro-caspase 3 and cleaved caspase 3) in aortic tissue, effects reversed by EGCG. Additionally, EGCG enhanced expression of Kruppel-like factor 4 (KLF4), a key regulator of vascular homeostasis, on the lumen surface. Collectively, oral SiO₂ NP exposure exacerbates early atherosclerotic progression through metabolic dysregulation and activation of autophagy-apoptosis pathways, while EGCG counteracts these effects by restoring metabolic balance and regulating KLF4.

Energy drinks (EDs), widely consumed for their stimulant effects, typically contain caffeine alongside taurine, guarana, and other bioactive compounds. While generally regarded as safe, growing evidence links chronic EDs consumption to significant cardiovascular risks. Caffeine, the primary active ingredient, acts through adenosine receptor antagonism and increased calcium release, potentially provoking arrhythmias and myocardial stress. Taurine and other additives further influence cardiac excitability and contractility. This systematic review, conducted under PRISMA 2020 guidelines, investigated the cardiac histopathological consequences of chronic EDs use. A literature search spanning 2021 to March 2025 across PubMed, Google Scholar, and Scopus identified studies reporting EDs-related cardiac effects. Data extraction and analysis revealed consistent associations with QTc prolongation, atrial and ventricular arrhythmias, myocardial infarction, Takotsubo cardiomyopathy, and hypertensive episodes-even in young, healthy individuals. Animal studies support these findings, showing myocardial necrosis, myofiber disarray, mitochondrial damage, and inflammation, particularly when EDs are combined with alcohol. Notably, similarities between EDs and cocaine emerged, including shared mechanisms involving ion channel blockade, sympathetic overactivation, vasoconstriction, and prothrombotic states. Chronic use of either substance can result in structural heart damage and remodelling. Although EDs and cocaine differ in legal status and potency, their overlapping cardiovascular effects warrant greater clinical awareness and public education. Excessive EDs consumption poses a real cardiotoxic risk, especially in vulnerable populations, underscoring the need for further human research and potential regulatory consideration.

Heart failure (HF) is a major public health concern marked by substantial morbidity and mortality. Emerging evidences suggest that copper (Cu) may be implicated in cardiovascular diseases, but its relationship with HF remains inadequately understood. This study was conducted to investigate the association between serum copper levels and the prevalence of HF, while exploring potential underlying mechanisms using network toxicology. Data were derived from 5139 participants aged 18-80 years in the NHANES 2011-2016 cycle. Serum copper levels were measured using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). Logistic regression and restricted cubic spline models were employed to evaluate the association between serum copper and HF. A network toxicology approach, incorporating database mining (CTD and ChEMBL), protein-protein interaction (PPI) network analysis, Gene Ontology (GO), and KEGG pathway enrichment, was utilized to elucidate potential molecular mechanisms. Elevated serum copper levels were significantly associated with increased prevalence of HF (OR 1.08, 95% CI 1.03-1.13; p = 0.0008). A significant sex-based interaction was observed, with a stronger association evident among males. Through in silico analysis, a total of 108 copper-related HF target genes were identified, with TP53, IL-1B, IL-6, TNF, AKT1, and ALB recognized as hub genes. Enriched KEGG pathways included lipid metabolism and atherosclerosis, apoptosis, MAPK signaling, ROS-mediated chemical carcinogenesis, and AGE-RAGE signaling in diabetic complications. Mechanistically, copper-induced oxidative stress, apoptosis, and immune dysregulation were implicated in HF pathogenesis. Serum copper levels demonstrate an independent association with HF prevalence. However, due to the cross-sectional design of the study, causal inference cannot be established. Network toxicological analysis highlights key biological pathways such as oxidative stress and apoptosis, offering mechanistic insights into the role of copper in HF development.

Ferroptosis is considered to be a pathological mechanism of myocardial ischemia-reperfusion injury (MI/RI). Previous studies have shown that death-associated protein kinase 1 (DAPK1) was involved in MI/RI development, but the underlying mechanism remains unclear. Mice with ligation of the left anterior descending artery followed by reperfusion, and HL-1 cells subjected to hypoxia/reoxygenation (H/R) induction were used as MI/RI animal and cell models, respectively. The pathological status of the mouse heart was evaluated by TTC staining, HE staining and echocardiography. Cell viability was examined using CCK-8. DAPK1, SRY-box transcription factor 4 (SOX4) and ferroptosis-related indicators were determined using RT-qPCR, western blot, commercial kits and DCFH-DA method. The interaction between SOX4 and DAPK1 promoter was validated using dual luciferase assay and ChIP assay. In MI/RI mice and H/R-induced cardiomyocytes, DAPK1 and SOX4 expression was abnormally elevated compared with that in control groups. In addition, silencing of DAPK1 or SOX4 improved cardiomyocyte injury and attenuated ferroptosis in H/R-induced cardiomyocytes. At the molecular levels, SOX4 could promote DAPK1 transcription and elevate DAPK1 expression via interacting with the DAPK1 promoter. Furthermore, SOX4 knockdown alleviated cardiomyocyte injury and mitigated ferroptosis through inhibiting DAPK1 expression, thereby relieving MI/RI in mice. Our results reveled that SOX4 promoted cardiomyocyte injury and exacerbated ferroptosis, thereby intensifying MI/RI through increasing DAPK1 expression.

This study aims to mine and analyze adverse events (AEs) of argatroban based on the FAERS database to better understand its safety and potential risks in the real-world. Data from the first quarter of 2004 to the third quarter of 2024 were collected, and researchers employed various signal mining methods such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). The study collected 54,336,884 reports of AEs, of which 2,233 were related to argatroban. Signal mining identified 110 Preferred Terms involving 25 system organ classes. There were most reports involving adults (≥ 65 years), with a slightly higher proportion in men than women. We identified known AEs, including prolonged coagulation time, hemorrhage, abnormal hepatic function. New potential AE signals were identified, such as vascular pseudoaneurysm, retroperitoneal hematoma, gangrene, thrombotic thrombocytopenic purpura, acute cardiac failure, atrial septal defect, rhabdomyolysis. The median time to event was 2.00 days, with the majority of AEs occurring within 30 days. Analysis of the FAERS database identified argatroban-associated AEs, including newly identified potential risks with the aim of enhancing clinicians' and pharmacists' awareness of drug-related risk signals and facilitate timely preventive and treatment interventions for patient safety.

Exposure to fine particulate matter (PM2.5) is associated with adverse cardiovascular outcomes, but the effectiveness of individual-level interventions to reduce exposure remains unclear. This meta-analysis aimed to assess the effects of four distinct categories of PM2.5 interventions on cardiovascular health including high-efficiency particulate air (HEPA) filters, respiratory protective equipment, improved cookstoves, and other behavioral PM2.5 reduction methods. We systematically searched PubMed, Embase, Web of Science, and the Cochrane library for studies published between December 2002 and March 2025 that reported the cardiovascular effect of PM2.5 reduction. Intervention methods were categorized based on their mechanisms of action and implementation settings. The primary outcomes were systolic blood pressure (SBP) and diastolic blood pressure (DBP), with secondary outcomes including endothelial function indices, heart rate variability (HRV), and inflammatory markers. A total of 72 trials involving 6,063 participants (age range: 12.4-82 years) were included. Overall, PM2.5 reduction interventions significantly decreased SBP by 1.97 mmHg (95% CI: -2.89, -1.05) and DBP by 1.08 mmHg (95% CI: -1.80, -0.35). Among secondary outcomes, C-reactive protein (CRP) decreased significantly (MD = -0.03mg/dl, 95% CI: -0.06, -0.00, P = 0.042), while no significant changes were observed in interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), or HRV. Subgroup analyses revealed differential effects by intervention type: Air filtration interventions showed the largest effect on SBP (MD = -1.94mmHg, 95% CI: -3.33, -0.55, P = 0.006) compared to other interventions. These findings suggest that PM2.5 reduction interventions could lower blood pressure and reduce markers of systemic inflammation, indicating that personal-level interventions may provide measurable cardiovascular benefits, even with short-term implementation.

Myocardial infarction (MI), induced by ischemia and hypoxia of the coronary arteries, presents as myocardial necrosis. Patients often experience intense, prolonged retrosternal pain that is unrelieved by rest or nitrate therapy and is frequently associated with high blood myocardial enzyme levels. Physical effort may exacerbate this anxiety, increasing the likelihood of life-threatening consequences such as arrhythmias, shock, or cardiac failure. Chrysin, a natural flavonoid primarily found in honey and propolis, exhibits anti-inflammatory, antioxidant, anticancer, and antiviral properties. This study utilized MI models and various analytical techniques, including Western blotting, immunofluorescence, quantitative polymerase chain reaction (qPCR), and autodocking, to elucidate the molecular mechanisms underlying the action of chrysin in molecular interactions. Our results demonstrated that Chrysin alleviates apoptosis in cardiomyocytes by decreasing the Bax/Bcl-2 ratio and suppressing caspase-3 activation, actions facilitated by PPAR-γ activation and consequent overexpression of anti-apoptotic proteins. Furthermore, chrysin mitigates cardiac fibrosis by downregulating TGF-β1, collagen I, and α-SMA expression. These effects markedly diminish infarct size and improve heart function in ischemia-reperfusion damage models, ascribed to chrysin's activation of PPAR-γ and SIRT3, together with the regulation of β-catenin pathways. The preclinical data presented in this research establish a foundation for forthcoming clinical studies to assess the safety and effectiveness of chrysin in patients with myocardial infarction. This may facilitate the development of a novel treatment approach for treating MI.

Doxorubicin-induced cardiotoxicity (DIC) is pathologically characterized by oxidative stress and inflammatory cascades, creating an urgent need to identify therapeutic targets modulating these processes. While tumor necrosis factor alpha-induced protein 8 (TNFAIP8) has emerged as a regulator of inflammation and apoptosis, its functional role in DIC remains unexplored. This study systematically investigates TNFAIP8's cardioprotective mechanisms against DIC. A chronic DIC model was established in male C57BL/6 mice through intraperitoneal doxorubicin (DOX) administration (4 mg/kg weekly for 4 weeks; cumulative dose 16 mg/kg). TNFAIP8 knockdown was achieved via AAV9-delivered shRNA through tail vein injection. Multimodal assessment integrating echocardiography, histopathology analysis, and molecular profiling elucidated TNFAIP8's functional and mechanistic contributions. In DOX-induced cardiomyocytes, TNFAIP8 expression was upregulated. The absence of TNFAIP8 markedly reduced DOX-triggered oxidative stress and inflammatory responses. The potential protective mechanism of TNFAIP8 deficiency against DIC involves toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Importantly, administration of the TLR4 activator lipopolysaccharide (LPS) substantially reversed the cardioprotective effects observed with TNFAIP8 deletion. Our findings establish TNFAIP8 as a critical regulator of DIC pathophysiology through TLR4/NF-κB axis modulation. Pharmacological TNFAIP8 inhibition represents a viable therapeutic strategy for mitigating chemotherapy-induced cardiac dysfunction. Future investigations should prioritize developing cardiac-targeted TNFAIP8 inhibitors and validating their efficacy in large-animal DIC models.