Cardiovascular Toxicology最新文献

Endothelial cell (EC) injury is highly significant in both health toxicology and cardiovascular disease. In the context of environmental and occupational health, ECs are frequently the frontline responders to pathogens and toxicants. Upon exposure to such agents, endothelial dysfunction ensues, triggering a cascade of cellular fates including pyroptosis, apoptosis, and necroptosis, which together constitute PANoptosis. The NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome is a sentinel of cellular stress and is activated in response to environmental pollutants and chemical toxins. Notably, strategies aimed at suppressing NLRP3 activation, such as the potential deployment of specific antidotes or detoxifying agents, have shown promise in impeding endothelial injury and halting the progression of cardiovascular diseases (CVDs). In this review, we summarize the role of NLRP3 in endothelial injury, highlight its PANoptosis ramifications, and partially discuss its relationship with vascular toxicity, which may aid in the prevention and treatment of vascular disorders and toxicology.

High-mobility group protein B2 (HMGB2) has been confirmed to participate in regulating the process of myocardial ischemia/reperfusion (I/R) injury. However, the more roles and mechanisms of HMGB2 in myocardial I/R injury need to be further revealed. Cardiomyocytes (HL-1) were cultured under hypoxia/reoxygenation (H/R) conditions, and myocardial I/R injury mouse model was established by ligation of the left anterior descending coronary artery. The protein levels of HMGB2 and kruppel-like factor 9 (KLF9) were determined by western blot. Cell viability and apoptosis were examined by CCK8 assay and flow cytometry. The levels of inflammatory factors and ferroptosis-related markers were tested to assess cell inflammation and ferroptosis. The interaction between KLF9 and HMGB2 promoter was evaluated by ChIP assay and dual-luciferase reporter assay. HMGB2 was higher expressed in H/R-induced HL-1 cells and its silencing could suppress H/R-induced HL-1 cell apoptosis, inflammation, and ferroptosis. KLF9 had binding sites in HMGB2 promoter region, which could increase HMGB2 expression by enhancing its transcription. Silencing of KLF9 inhibited H/R-induced HL-1 cell apoptosis, inflammation, and ferroptosis, while these effects were reversed by overexpressing HMGB2. In addition, animal study revealed that interference of KLF9 alleviated myocardial tissues damage and fibrosis in I/R injury mice models by reducing HMGB2 expression. Collectively, our study indicated that KLF9 promoted myocardial I/R injury by aggravating cardiomyocyte apoptosis, inflammation, and ferroptosis through promoting HMGB2 transcription.

Novel tobacco products (NTPs) have recently been on the rise appealing to a variety of users, including pregnant women and women of childbearing age, who deem these products to be a safe/safer alternative to traditional smoking. To this end, several studies have made advances toward proving the invalidity of these claims, especially in the context of cardiovascular disease. However, an area that has yet to be extensively explored is maternal/in utero exposure to these devices and the cardiovascular health outcomes on the offspring into their adult life. Herein, our aim is to critically assess the literature to identify and discuss the cardiovascular health risks that the offspring exhibits as a result of in utero exposure to NTPs. These studies have been summarized as a comprehensive review.

Cobalt is a prevalent environmental metal with known toxicological potential. Inflammation plays a key role in the pathophysiology of cardiovascular disease (CVD) and chronic kidney disease (CKD). However, the relationships between blood cobalt concentrations, inflammatory indicators, and their roles in CVD and CKD remain inadequately characterized. This study aimed to evaluate the associations between blood cobalt concentrations and the prevalence of CVD and CKD and to explore the mediating role of inflammatory indicators in these associations. Data from 6689 participants were obtained from the National Health and Nutrition Examination Survey 2015-2018. Restricted cubic splines and multivariate logistic regression models were used to assess the associations between blood cobalt exposure, CVD, CKD, and inflammatory markers. Generalized additive models were applied to investigate potential nonlinear relationships. The receiver operating characteristic analysis assessed the discriminatory ability of blood cobalt levels for CVD and CKD. Mediation analysis was conducted to examine whether inflammatory indicators mediate the association between blood cobalt and CVD/CKD. Multivariate logistic regression analysis showed that higher blood cobalt levels (OR = 1.50, 95% CI 1.22-1.85, P < 0.001) and NMLR (OR = 1.34, 95% CI 1.07-1.68, P = 0.010) were significantly associated with a higher prevalence of CVD. For CKD, blood cobalt (OR = 1.74, 95% CI 1.44-2.11, P < 0.001), SII (OR = 1.43, 95% CI 1.18-1.73, P < 0.001), NLR (OR = 1.73, 95% CI 1.42-2.10, P < 0.001), and NMLR (OR = 1.63, 95% CI 1.33-2.00, P < 0.001) were all significantly associated with a higher prevalence of CKD. Blood cobalt levels showed significant positive correlations with SII, NLR, PLR, and NMLR. Specifically, SII (β = 49.93, 95% CI 26.91-72.94, P < 0.001), NLR (β = 0.21, 95% CI 0.13-0.30, P < 0.001), and NMLR (β = 0.20, 95% CI 0.13-0.27, P < 0.001) exhibited significant increases. Mediation analysis indicated that SII, NLR, NMLR, and LMR significantly mediated the association between log_BCo and both CVD and CKD (P < 0.05). Notably, NMLR had the strongest mediating effect in both CVD and CKD, with a mediation effect percentage: 13.42% (P < 0.001) in CVD and 11.76% (P < 0.001) in CKD. Blood cobalt concentrations are significantly associated with the prevalence of cardiovascular disease and chronic kidney disease. Inflammation may play a mediating role in these associations. These findings highlight the potential contribution of inflammation to cobalt-related cardiovascular and kidney disease risks.

Pregnancy requires metabolic and endocrine changes that must occur to support fetal growth and development. Aberrations in these necessary modifications can impact maternal health and fetal growth. Exposure to toxicants during pregnancy can negatively affect fetal health and development, but studies on electronic cigarette (e-cig) exposure is limited. We hypothesized that maternal e-cig exposure during gestation leads to hormonal and redox imbalance and negatively impacts fetal development. Pregnant Sprague-Dawley rats were exposed to e-cig aerosols (1227 ± 131 mg/m³) or HEPA-filtered air for 90 min from gestational day (GD) 10-19 for a total of 6 days. Dams were euthanized on GD 20 and dam serum, liver, lung, ovaries, and placental tissue were collected for analysis. Fetal mass, placental mass, and sex ratios were assessed. Fetal and placental mass were significantly decreased in e-cig exposed compared to sham-control (2.61 ± 0.19 g vs. 3.37 ± 0.09 g and 0.62 ± 0.03 g vs. 0.70 ± 0.02 g, respectively). Placental xanthine oxidase (XO) activity was significantly increased in e-cig exposed compared to sham-control (5.29 ± 0.27 µU/mL vs. 4.28 ± 0.36 µU/mL). Circulating prolactin (PRL) levels of e-cig exposed dams were significantly decreased compared to sham-control (2.40 ± 0.06 ng/mL of plasma vs. 3.83 ± 0.64 ng/mL of plasma). Maternal e-cig inhalation exposure during gestation negatively impacted fetal growth, increased placental XO activity, and decreased circulating PRL levels. These data demonstrate two potential mechanisms that could lead to the observed reduction in fetal growth following maternal exposure: potential redox imbalance within the placenta and/or hormonal imbalance directly affects fetal growth and potentially influences growth later in life.

Environmental toxins such as heavy metals, industrial pollutants, pesticides, and environmental chemicals are becoming recognized as key contributors to cardiotoxicity, with considerable implications for worldwide cardiovascular health. Humans are unintentionally exposed to environmental toxins, which have a variety of cardiopathologic effects. These poisons cause oxidative stress, inflammation, mitochondrial dysfunction, and dysregulation of important physiological pathways which ultimately contribute to cardiac dysfunction and diseases. Natural compounds originating from medicinal plants, microbes, and marine organisms have emerged as promising cardioprotective agents. These bioactive chemicals exhibit potent anti-oxidant, anti-inflammatory, and cardio-regenerative activities, which target molecular mechanisms involved in cardiotoxicity. Phytochemicals such as terpenoids, polyphenols, flavonoids, and alkaloids, as well as bioactive peptides and microbial metabolites, have shown promise in pre-clinical and clinical investigations for preventing toxin-induced cardiac damage. Therefore, this review highlights the mechanisms of environmental toxin-induced cardiotoxicity and the novel therapeutic agents for the prevention and treatment of environmental toxin-induced cardiotoxicity.

Immune Checkpoint Inhibitor (ICI)-related cardiotoxicity has a high mortality rate, making early prediction crucial for improving patient prognosis. However, early prediction models are currently lacking in clinical practice. This study aims to develop an early prediction model for ICI-related cardiotoxicity using the eXtreme Gradient Boosting (XGBoost) algorithm. Retrospective analysis was conducted on patients who received ICI therapy between January 2020 and December 2023. The population was categorized into a cardiotoxicity group and a non-cardiotoxicity group based on the presence of cardiac biomarkers and electrocardiogram abnormalities that could not be attributed to other diseases within 30 days after initiation ICI therapy. The dataset was split into training (70%) and testing (30%) sets. Logistic Regression (LR), Random Forest (RF), and XGBoost models were constructed in Python, with variables selected based on each model's characteristics. The models were compared based on predictive performance, which was measured by area under the curve (AUC) and decision curve analysis (DCA). The best model was explained using SHapley Additive exPlanation (SHAP). A total of 419 patients were included. The XGBoost model demonstrated the highest predictive performance with an AUC of 0.83, outperforming LR (AUC: 0.80) and RF (AUC: 0.74) models. DCA confirmed the XGBoost model's superior net benefit. Among the selected predictors, cardiac troponin T (cTnT) emerged as the most important variable, demonstrating the highest feature importance. The XGBoost model proposed could assist clinicians in personalized risk stratification for patients on ICI therapy, facilitating precise monitoring of cardiotoxicity and tailored treatment strategies.

Coronary heart disease (CHD) is a prevalent cardiovascular' condition characterized by high morbidity and mortality rates, with a significant genetic component. The VEGFA gene plays a crucial role in the development of CHD. This study aims to evaluate the influence of VEGFA gene polymorphisms on CHD susceptibility. Peripheral blood samples were collected from 479 CHD patients and 479 healthy controls. We genotyped four VEGFA single nucleotide polymorphisms (SNPs): rs833068, rs833070, rs3025021, and rs3025030, using the Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the association between these SNPs and CHD risk. Multifactor dimensionality reduction (MDR) was employed to analyze potential SNP-SNP interactions. The rs833068 SNP was found to be associated with a reduced risk of CHD (OR 0.46, p = 0.013), whereas the rs3025021 (OR 1.32, p = 0.031) and rs3025030 (OR 1.30, p = 0.032) SNPs were linked to an increased risk. The stratified analysis revealed that rs833068 decreased CHD risk in individuals aged < 61 years, those with a BMI ≥ 24, non-smokers, non-drinkers, and patients with diabetes, but increased the risk in hypertensive individuals. The rs833070 SNP significantly increased CHD risk in non-smokers and non-drinkers. Rs3025021 was associated with an increased CHD risk in subjects with a BMI < 24, smokers, drinkers, and diabetics. Rs3025030 was found to increase CHD susceptibility in aged > 61 years, males, those with a BMI ≥ 24, and drinkers. MDR analysis identified a combination of rs833068, rs3025021, and rs3025030 as the most predictive model for CHD. Polymorphisms in the VEGFA gene are associated with CHD risk in the Chinese Han population, offering a novel perspective for CHD diagnosis.

Anthracycline anti-cancer drugs, which are used in cancer chemotherapy, frequently cause cardiotoxicity, the incidence of which depends on cumulative doses. TXB-001 is a new candidate polymer-conjugated pirarubicin (THP) with higher THP purity and content compared to previous P-THP (polymerized THP) and is expected to exhibit lower cardiotoxicity and higher efficacy against cancer cells. We examined the effects of TXB-001 on cardiac function and the pharmacokinetics after its intravenous administration compared with those of existing anthracyclines (doxorubicin (DOX), DOXIL (liposomal formulation of DOX), THP) in mice. Echocardiography and electrocardiography showed that DOX caused cardiac dysfunction in mice, with associated changes in organ weights, blood chemical parameters, and mRNA/protein expressions. DOXIL and THP induced similar, but weaker changes than DOX. TXB-001 did not significantly affect cardiac function or associated changes under the conditions of this study. The results of the pharmacokinetic evaluation revealed that the distributions of DOXIL and TXB-001 from plasma to heart tissue were lower than those of DOX and THP, while the distribution of TXB-001 was lower than that of DOXIL. Furthermore, TXB-001 did not show cardiac accumulation in contrast to DOXIL. In addition, the anthracycline exposure level of TXB-001 in the heart was lower than those of DOX, DOXIL, and THP, with less exposure being regarded as one reason for the low or no cardiotoxicity of TXB-001 in mice. Collectively, these results suggest the potential of TXB-001 as an anti-cancer drug with fewer side effects than anthracyclines, particularly cardiotoxicity. Novel TXB-001 may become an effective anti-cancer drug with fewer cardiotoxicity.

Cardiac fibrosis, oxidative stress, and cardiomyocyte apoptosis are key contributors to the progression of doxorubicin (DOX)-induced cardiotoxicity. ELABELA (ELA) is an early endogenous ligand of apelin receptor (APJ/APLNR), which is a G protein-coupled receptor with seven transmembrane domains. Our present study aimed to investigate the protective role and underlying mechanism of ELA-32 in mitigating oxidative stress and fibrosis associated with DOX-induced cardiotoxicity. Using a mouse model of chronic DOX cardiotoxicity (5 mg/kg, i.p, once a week for four times, the total cumulative dose is 20 mg/kg), it was found that exogenous administration of ELA-32 using a microinjection pump significantly improved cardiac function, reduced oxidative stress, and myocardial fibrosis, and enhanced survival. Furthermore, pretreatment with ELA-32 peptide protected rat cardiomyocytes (H9C2 cells) from DOX-induced cytotoxicity in vitro. However, these cardioprotective effects of ELA-32 were no longer observed after activation of the Smad signaling pathway using TGF-β1. In summary, ELA-32 attenuated DOX-induced cardiac fibrosis through by modulating the TGF-β/Smad signaling pathway, thus highlighting its potential as a therapeutic agent for preventing chronic DOX-related cardiotoxicity.