Cardiovascular Toxicology最新文献

Circular RNAs (circRNAs) play an important role in the progression of atherosclerosis (AS). This study aimed to explore the exact role and mechanism of circ_0002984 in oxidized low-density lipoprotein (ox-LDL)-mediated human vascular smooth muscle cells (HVSMCs). The model of smooth muscle cell phenotype switching was constructed by treating HVSMCs with ox-LDL. The levels of circ_0002984, let-7a-5p, and kruppel-like factor 5 (KLF5) were measured by quantitative real-time PCR or western blot assay. Cell proliferation, migration, and apoptosis were detected by Cell Counting Kit-8 (CCK-8), EdU staining, wound healing assay, transwell assay, and flow cytometry. The expression of cleaved-caspase-3 and KLF5 was examined by western blot. The relationship between let-7a-5p and circ_0002984 or KLF5 was verified by dual-luciferase reporter assay or RIP assay. The results showed that circ_0002984 and KLF5 were up-regulated, while let-7a-5p was down-regulated in AS patients and ox-LDL-disposed HVSMCs. Silence of circ_0002984 suppressed proliferation and migration, and promoted apoptosis in ox-LDL-stimulated HVSMCs. Moreover, circ_0002984 sponged let-7a-5p to regulate the proliferation, migration, and apoptosis in ox-LDL-resulted HVSMCs. In addition, KLF5 was a target of let-7a-5p and its overexpression reversed the effect of let-7a-5p on the proliferation, migration, and apoptosis in ox-LDL-treated HVSMCs. Also, circ_0002984 positively regulated KLF5 expression by absorbing let-7a-5p. The promotion effect of circ_0002984 on the proliferation and migration of ox-LDL-treated HVSMCs was reversed by KLF5 silencing. Taken together, depletion of circ_0002984 inhibited the proliferation and migration of ox-LDL-stimulated HVSMCs, which might be achieved by modulating the let-7a-5p/KLF5 axis.

Cardiotoxicity is a serious challenge cancer patients face today. Various factors are involved in cardiotoxicity. Circular RNAs (circRNAs) are one of the effective factors in the occurrence and prevention of cardiotoxicity. circRNAs can lead to increased proliferation, apoptosis, and regeneration of cardiomyocytes by regulating the molecular pathways, as well as increasing or decreasing gene expression; some circRNAs have a dual role in cardiomyocyte regeneration or death. Identifying each of the pathways related to these processes can be effective on managing patients and preventing cardiotoxicity. In this study, an overview of the molecular pathways involved in cardiotoxicity by circRNAs and their effects on the downstream factors have been discussed.

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes.

Previous studies have found a possible association between nickel and metabolic syndrome (MetS), but with conflicting results. No studies have determined whether nickel exposure increases the prevalence of MetS in the general U.S. population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to assess the association between urinary nickel and MetS. Since urinary nickel levels were presented as a skewed distribution, they were normalized using a logarithmic transformation. Weighted multivariate logistic models, restricted cubic spline, threshold effect analysis, and subgroup analyses were used to examine the association between urinary nickel concentration and the risk of MetS and its components. Based on data from 1577 participants, individuals in the second, third, and fourth quartiles of urinary nickel had an adjusted OR for MetS of 1.42 (95% CI: 0.88, 2.28), 2.00 (95% CI: 1.22, 3.28), and 1.68 (95% CI: 1.05, 2.70), respectively, representing an inverted "L"-shaped nonlinear dose-response relationship with an inflection point at 0.2141 ng/L. Patients over the age of 40, males, less educated, and smokers are more susceptible to nickel exposure. In addition, there were significant associations between nickel and most components of the MetS, with the strongest to weakest correlations being high fasting glucose, reduced high-density lipoprotein, abdominal obesity, and elevated blood pressure; however, there was no significant correlation between nickel and hyperlipidemia. In conclusion, environmental nickel exposure increases the prevalence of MetS in U.S. adults, particularly in males over 40 years of age, those with less education, and smokers.

The impact of metal exposure on cardiovascular diseases has become an increasingly concerning topic. To date, few studies have investigated the relationship between the copper-to-zinc ratio and CVD (Cardiovascular disease). This China multi-ethnic cohort study explored the association between the copper-to-zinc ratio and CVD in Chinese adults. The study included a sample size of 9878 people. Logistic regression analysis was used to examine the correlation between urinary copper, urinary zinc, and the copper-to-zinc ratio and CVD prevalence. Restricted cubic spline (RCS) analysis was used to investigate the potential dose-response relationships among copper-to-zinc ratio, urinary copper, urinary zinc, and CVD prevalence. In addition, the least absolute shrinkage and selection operator (LASSO) regression method was used to identify significant risk factors associated with CVD, leading to the development of a nomogram. The predictive performance of the nomogram model for CVD was assessed using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Compared with the copper-to-zinc ratio in Q1, the copper-to-zinc ratio in Q4 was associated with CVD after adjusting for all potential confounders (Model 3) (Q4, odds ratio [OR] 0.608, 95% confidence interval [CI] 0.416-0.889, P = 0.010). After adjusting for all potential confounders (Model 3), urinary copper levels in Q4 were associated with CVD (Q4, odds ratio [OR] 0.627, 95% confidence interval [CI] 0.436-0.902, P = 0.012). No significant difference was found between urinary zinc levels and CVD. The RCS showed a linear dose-response relationship between the copper-to-zinc ratio and CVD (P for overall = 0.01). The nomogram based on the influencing factors examined with LASSO showed good predictive power, and the AUC was 76.3% (95% CI 73.7-78.9%). Our results suggest that there is a significant linear negative correlation between the copper-to-zinc ratio and CVD in Chinese adults and that it has good predictive value for CVD.

This research focused on investigating the effects of sevoflurane (Sev) on myocardial autophagy levels after myocardial ischemia reperfusion (I/R) injury via the microRNA-542-3p (miR-542-3p)/ADAM9 axis. Mice underwent 30 min occlusion of the left anterior descending coronary (LAD) followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC) staining. Cardiac function was examined by echocardiography. Cardiac markers and oxidative stress factors were evaluated by ELISA. Autophagy-associated factors were detected by western blot. Relationship between miR-542-3p and ADAM9 was tested by dual-luciferase reporter gene assay, RT-qPCR, and western blot. Sev treatment ameliorated cardiac dysfunction, myocardial oxidative stress, and histopathological damages, decreased myocardial infarction size and myocardial apoptotic cells after myocardial I/R injury. Sev treatment elevated miR-542-3p expression and decreased ADAM9 expression in myocardial tissues after myocardial I/R injury. miR-542-3p overexpression could enhance the ameliorative effects of Sev on myocardial injury and myocardial autophagy in I/R mice. miR-542-3p targeted and negatively regulated ADAM9 expression. ADAM9 overexpression reversed the ameliorative effects of miR-542-3p up-regulation on myocardial injury and myocardial autophagy in Sev-treated I/R mice. Sev treatment could ameliorate myocardial injury and myocardial autophagy in I/R mice, mediated by mechanisms that include miR-542-3p up-regulation and ADAM9 down-regulation.

Human aortic vascular smooth muscle cells (HA-VSMCs) play vital roles in the pathogenesis of vascular diseases, including Atherosclerosis (AS). Circular RNAs (circRNAs) have been reported to regulate the biological functions of HA-VSMCs. Therefore, this study aimed to explore the role and mechanism of hsa_circRNA_102353 (circ_0007765) in platelet-derived growth factor-BB (PDGF-BB)-induced HA-VSMCs. Circ_0007765, microRNA-654-3p (miR-654-3p), and Fibroblast Growth Factor Receptor Substrate 2 (FRS2) expression were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferative ability, invasion, and migration were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and wound healing assays. CyclinD1, MMP2, and FRS2 protein levels were assessed using a Western blot assay. Binding between miR-654-3p and circ_0007765 or FRS2 was predicted by Circinteractome or TargetScan, and verified using dual-luciferase reporter and RNA pull-down assays. PDGF-BB induced HA-VSMC proliferation, invasion, and migration. Circ_0007765 and FRS2 expression levels were increased in PDGF-BB-treated HA-VSMCs, and the miR-654-3p level was reduced. Moreover, circ_0007765 absence hindered PDGF-BB-induced HA-VSMC proliferation, invasion, and migration in vitro. At the molecular level, circ_0007765 increased FRS2 expression by acting as a sponge for miR-654-3p. Our findings revealed that circ_0007765 boosted PDGF-BB-induced HA-VSMC proliferation and migration through elevating FRS2 expression via adsorbing miR-654-3p, providing a feasible therapeutic strategy for AS.

Iron deficiency (ID) is common in patients with acute myocardial infarction (AMI). It is unknown whether patients with AMI combined with ID will benefit from iron supplementation therapy. This study aimed to assess the relationship between iron therapy and mortality in AMI patients. Retrospective analysis was performed in subjects screened from the Medical Information Mart in Intensive Care-IV database. The data were obtained from ICU patients admitted to Beth Israel Deaconess Medical Center between 2008 and 2019. The patients were divided into two groups according to iron treatment exposure. Propensity score matching (PSM) was performed in the original cohort at a 1:1 ratio. Univariate and multivariate analyses were performed to adjust for confounding factors. The primary outcome was 28-day mortality. A total of 426 patients were included in this study. After 1:1 PSM, 208 patients were analyzed. Iron treatment was associated with a lower risk of 28-day mortality (9 deaths (8.65%) in the iron treatment group vs. 21 deaths (20.19%) in the non-iron treatment group; HR = 0.39; 95% CI = 0.17-0.89; p = 0.025) and in-hospital mortality (4 deaths (3.85%) in the iron treatment group vs. 12 deaths (11.54%) in the non-iron treatment group; OR, 0.15; 95% CI, 0.03-0.74; p = 0.029). Iron treatment was associated with reduced 28-day mortality in patients with AMI combined with ID. Iron treatment had no significant effect on the length of hospitalization or the length of ICU stay. Prospective studies are needed to verify this conclusion.

Objective: This study aimed to explore the potential role of CYP3A5 (c. 6986A>G) gene polymorphism in predicting kidney function impairment in patients with hypertension who did not have elevated serum cystatin C.

Methods: We recruited a group of patients with hypertension who did not have elevated cystatin C and analyzed the CYP3A5 (c. 6986A>G) gene polymorphism. Chi-square tests were used to compare the clinical characteristics and genotypic distribution between the two groups. Logistic regression analysis was used to explore the association between CYP3A5 (c.6986A>G) gene polymorphism and renal function impairment in hypertension with non-elevated cystatin.

Results: In patients with hypertension who participated in the study, there was a significant association between CYP3A5 (c. 6986A>G) gene polymorphism and kidney function impairment (p < 0.05). Patients with the CYP3A5 (c. 6986A>G) mutation display a greater risk of kidney function impairment.

Conclusion: CYP3A5 (c. 6986A>G) gene AA homozygote polymorphism significantly increases risk of kidney function impairment in patients with hypertension with normal cystatin C. However, further studies are needed to validate this association and to further understand the mechanism of CYP3A5 (c. 6986A>G) gene polymorphism in kidney function impairment in patients with hypertension.

Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α₁-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.