Cardiovascular Toxicology最新文献

Heavy metals were toxic environmental pollutants capable of entering the human body, posing significant risks to human health. Life's Essential 8 (LE8) score is a new comprehensive index constructed for quantifying cardiovascular health (CVH). However, the association between heavy metals mixtures and LE8 appears ambiguous. To investigated the association between heavy metals and cardiovascular health in US population. Urinary heavy metals concentrations (barium, cadmium, cobalt, manganese, molybdenum, lead, antimony, strontium, thallium, tin, tungsten, uranium, cesium) were Ln-transformed and LE8 was consisted of eight metrics. Single and multivariate linear regression, weighted quantile sum (WQS) and Bayesian kernel machine regression models (BKMR) were utilized to assess the association between single and mixed exposure of thirteen heavy metals concentrations and LE8. In 4339 participants from National Health and Nutrition Examination Survey 2007-2018, single urinary heavy metals barium, cadmium, cobalt, lead, antimony, strontium, tin, tungsten, uranium and cesium showed a significant negative association with LE8. WQS models showed heavy metals mixture was negatively associated with LE8 (β = - 2.720, 95% CI - 3.660, - 1.790). BKMR analysis also demonstrated a downward trend of heavy metals mixture and LE8. Both WQS analyzed weights and the conditional posterior inclusion probabilities (condPIP) of BKMR showed that cadmium (37.78%, condPIP = 1.000), barium (24.56%, condPIP = 0.537) and uranium (14.71%, condPIP = 0.646) contributed most for these negative associations. Single and mixed heavy metals, especially cadmium, barium and uranium were negatively associated with LE8 score, a new comprehensive CVH index, predicting an increasing risk of cardiovascular diseases.

Ascending aortic dilation (AAD) is a complex and life-threatening condition, representing a significant risk factor for acute aortic syndromes. Due to its asymptomatic nature, early diagnosis is frequently missed. Serum diagnostic biomarkers play a crucial role in disease diagnosis, and proteomics offers a valuable approach for identifying such biomarkers in blood samples. In this study, we collected serum samples from patients with AAD, thoracic ascending aortic dissection (TAAD), and healthy controls, using label-free proteomics to identify serum proteins. Differentially abundant proteins (DAPs) were identified between AAD, TAAD, and control groups. Functional analysis of DAPs was performed using the GO and KEGG databases. Compared to controls, 40 DAPs were found in AAD and 52 in dissection. Further analysis showed that the DAPs in AAD are involved in biological processes such as antibacterial humoral response, nucleosome assembly, and inflammatory response, while the DAPs in TAAD are involved in protein localization to CENP-A containing chromatin and negative regulation of megakaryocyte differentiation, etc. The protein expression profiles of TAAD and AAD were directly compared, leading to the identification of 37 DAPs. GO and KEGG analyses were also performed on these proteins. A significant overlap in protein expression was observed between AAD and dissection. Additionally, NUP188 was significantly down-regulated in AAD, and receiver operating characteristic (ROC) curve analysis suggests it may serve as a diagnostic biomarker for AAD.

The pharmaceutical industry is evolving with the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT-interval prolongation as a main arrhythmogenicity marker is being challenged. In addition, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as a more comprehensive approach for arrhythmogenicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess the potential arrhythmogenic effect of drug-induced impact on ionic currents and electrophysiological intercellular coupling. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modeling. We show, using the examples of lidocaine (100-300 μM) and Cyclophosphamide (639, 852 μM), that with the use of an integrative experimental and computer platform, it is possible to correctly display the clinical manifestations of side effects in advance.

In recent years, the cardioprotective effects of the volatile anesthetic sevoflurane (SEV) have been confirmed, yet its underlying molecular mechanisms remain incompletely elucidated. Notably, lncRNA LINC00265 has been identified as dysregulated in damaged cardiomyocytes, potentially contributing to disease progression. However, limited research has focused on the interplay between SEV and lncRNA LINC00265. The main objective of this study was to explore the mechanism and role of lncRNA LINC00265 in mediating the cardioprotective effects of SEV against myocardial injury. An in vitro hypoxia/reoxygenation (H/R) model was created in AC16 cells following pretreatment with varying concentrations of SEV. RT-qPCR was used to evaluate the levels of lncRNA LINC00265, miR-370-3p, IL-6, and TNF-α. The concentrations of CK-MB and cTnI were determined using ELISA. Cell viability was evaluated using CCK-8, and apoptosis was quantified by flow cytometry. Additionally, the relationship between lncRNA LINC00265 and miR-370-3p was confirmed using a dual-luciferase reporter assay. Prolonged hypoxia gradually rose in lncRNA LINC00265 levels, which was reversed by SEV pretreatment. SEV pretreatment mitigated H/R-induced decreases in cell viability, increases in apoptosis, and excessive production of IL-6, TNF-α, CK-MB, and cTnI. However, the protective effects of SEV were counteracted by lncRNA LINC00265 overexpression. A negative regulatory relationship between lncRNA LINC00265 and miR-370-3p was discovered. miR-370-3p overexpression mitigated diminished protective effects of SEV by elevated lncRNA LINC00265 in myocardial injury. lncRNA LINC00265 could diminish the protective effects of SEV against myocardial injury by functioning as a sponge for miR-370-3p.

Fine particulate matter (PM_2.5), defined as airborne particles with a diameter of ≤ 2.5 μm, represents a major constituent of air pollution and has been globally implicated in exacerbating public health burdens by elevating morbidity and mortality rates associated with respiratory and cardiovascular diseases (CVDs). Adverse health effects of PM_2.5 exposure manifest across diverse susceptibility profiles and durations of exposure, spanning both acute and chronic timelines. While prior reviews have predominantly focused on elucidating the toxicological mechanisms underlying PM_2.5-induced pathologies, there remains a paucity of comprehensive summaries addressing therapeutic interventions for cardiopulmonary damage. This review systematically synthesizes pharmacological agents with potential therapeutic efficacy against PM_2.5-induced pulmonary and cardiovascular injury. By integrating mechanistic insights with translational perspectives, this work aims to provide a foundational framework for advancing research into novel therapeutic strategies targeting PM_2.5-associated cardiopulmonary disorders.

Heart failure (HF) is a clinical syndrome resulting from cardiac overload and injury. The molecular mechanisms underlying ischemic HF remain unclear. Using the GSE116250 and GSE203160 datasets, we screened for differentially expressed genes (DEGs) in ischemic HF, identifying 132 overlapping genes. Through the protein-protein interaction (PPI) network, we screened nine hub genes-SPP1, POSTN, CCN2, FGF7, OGN, BMP2, LUM, TGFB2, and BMP7-that may serve as diagnostic biomarkers for HF. FGF7 and BMP7 expression levels were reduced, while TGFB2, OGN, and CCN2 expression levels were elevated in rat models of left anterior descending coronary artery ligation. Notably, Cell Counting Kit-8 and flow cytometry showed that TGFB2 knockdown promoted viability and inhibited apoptosis in oxygen glucose deprivation-induced H9c2 cells. Western blot analysis further demonstrated that TGFB2 knockdown decreased cleaved Caspase-3/Caspase-3 and Bax protein levels while increasing Bcl-2 protein expression. These findings reveal that TGFB2 knockdown mitigates ischemic HF by suppressing apoptosis, offering novel insights into the fundamental molecular mechanisms underlying HF.

Immune checkpoint inhibitors (ICIs) have demonstrated favorable outcomes in various cancers. However, it has been observed that ICIs may induce life-threatening cardiovascular toxicity. In this study, a meta-analysis was conducted to determine the risk of cardiovascular toxicities in patients exposed to ICIs or in combination with chemotherapy. PubMed, Cochrane Library, and Embase databases were searched from inception to September 24, 2023. This study was conducted in accordance with the PRISMA guidelines. A meta-analysis was conducted on the risk of cardiotoxicity in cancer patients. Data were pooled with a random-effect model. This protocol was registered prospectively in PROSPERO (CRD42023467319). The primary outcome was cardiotoxicity risk in observational studies with ICIs or combined with chemotherapy. The risk factors that affected the occurrence of cardiovascular toxicities were also examined. ICIs or combined with chemotherapy increased the cardiotoxicity risk compared with mono-chemotherapy (OR 1.47; 95% CI 1.05-2.06, p = 0.024). The risk of pericardial disease in cardiotoxic events (OR 1.99; 95% CI 1.23-3.22, p = 0.005) and thromboembolic events (OR 1.34; 95% CI 1.04-1.72, p = 0.025) was significantly increased. Smoking (OR 1.25; 95% CI 1.12-1.39, p < 0.001), previous heart disease (OR 2.01; 95% CI 1.64-2.46, p < 0.001), and lung cancer (OR 1.46; 95% CI 1.26-1.69, p < 0.001) were risk factors worthy of attention. ICIs or combined with chemotherapy show an elevated risk of cardiovascular toxicities. Patients who are smoking, diagnosed lung cancer, and having prior medical history of heart diseases need more attention.

Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Current therapies do not adequately resolve this problem and focus only on the optimal level of blood glucose for patients. Ferroptosis plays an important role in diabetes mellitus and cardiovascular diseases. However, the role of ferroptosis in DCM remains unclear. Differentially expressed ferroptosis-related genes (DE-FRGs) were identified by intersection of the GSE26887 dataset and the Ferroptosis Database. The associations between the DE-FRGs and immune cells in DCM, estimated via the CIBERSORTx algorithm, were analysed. Flow cytometry (FCM) was used to evaluate the infiltration of immune cells in myocardial tissues. The expression of DE-FRGs, glutathione peroxidase 4 and solute carrier family 7 member 11 was examined via real-time quantitative PCR and Western blotting. Three DE-FRGs were identified: heat shock protein family B (small) member 1 (HSPB1), microsomal glutathione S-transferase 1 (MGST1) and solute carrier family 40 member 1 (SLC40A1), which are closely linked to immune cells in DCM. In vivo, the levels of CD8 + T cells, B cells and regulatory T (Treg) cells were significantly decreased in the DCM group, whereas the levels of CD4 + T cells, M1 cells, M2 cells and monocytes were increased. Diabetes significantly decreased HSPB1 and MGST1 levels and increased ferroptosis compared with the Normal group. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviated high-fat diet (HFD)-induced cardiomyocyte injury and rescued ferroptosis. These findings suggest that the ferroptosis-related genes HSPB1 and MGST1 are closely related to immune cell infiltration and may be therapeutic targets for DCM.

Engineered nanomaterials (ENM) are capable of crossing the placental barrier and accumulating in fetal tissue. Specifically, the ENM nano-titanium dioxide (nano-TiO₂), has been shown to accumulate in placental and fetal tissue, resulting in decreased birthweight in pups. Additionally, nano-TiO₂ is an established cardiac toxicant and regulator of glucose homeostasis, and exposure in utero may lead to serious maladaptive responses in cardiac development and overall metabolism. The current study examines weight gain and cardiac function in male and female Sprague-Dawley rats exposed to 12 mg/m³ nano-TiO₂ or filtered air for 6 non-consecutive days in utero between gestational days 12-19. These animals were randomly assigned to receive a grain-based or high-fat diet (60%) between postnatal weeks 12-24 to examine the propensity for weight gain and cardiac response as adults. Our results show a sexually dimorphic response to weight gain with male rats gaining more weight after high-fat diet following in utero nano-TiO₂ exposure, and female rats gaining less weight on the high-fat diet respective of exposure. Male rats exposed to nano-TiO₂ in utero had reduced ejection fraction prior to diet when compared to air controls. Female rats subjected to in utero nano-TiO₂ exposure showed a significant decrease in cardiac output following 12 weeks of high-fat diet. Development of cardiovascular impairments and ultimately cardiac dysfunction and disease following in utero exposures highlights the need for occupational and environmental monitoring of nanoparticulate exposure.

Mercury is a significant environmental pollutant and public health threat, primarily recognized for its neurotoxic effects. Increasing evidence also highlights its harmful impact on the cardiovascular system, particularly in adults. Exposure to mercury through contaminated soil, air, or water initiates a cascade of pathological events that lead to organ damage, including platelet activation, oxidative stress, enhanced inflammation, and direct injury to critical cells such as cardiomyocytes and endothelial cells. Endothelial activation triggers the upregulation of adhesion molecules, promoting the recruitment of leukocytes and platelets to vascular sites. These interactions activate both platelets and immune cells, creating a pro-inflammatory, prothrombotic environment. A key outcome is the formation of platelet-leukocyte aggregates (PLAs), which exacerbate thromboinflammation and endothelial dysfunction. These processes significantly elevate cardiovascular risks, including thrombosis and vascular inflammation. This study offers a comprehensive analysis of the mechanisms underlying mercury-induced cardiotoxicity, focusing on oxidative stress, inflammation, and cellular dysfunction.