Cardiovascular Toxicology最新文献

Vascular regeneration after myocardial infarction (MI) is essential to improve myocardial ischemia, delay post-infarction ventricular remodeling, and improve the long-term prognosis of MI. Endothelial progenitor cells (EPCs) play important roles in the functional repair and homeostatic maintenance of the vascular endothelium. Exercise training stimulates EPC mobilization and increases the number of circulating EPCs, which has beneficial effects on the restoration of vascular integrity and hemodynamic reconstitution. After post-MI exercise training, cardiac function, the myocardial infarct area, and capillary density in the peri-infarct zone were measured. Bone marrow-derived EPCs were isolated from mice to measure the proliferation, migration, and in vitro angiogenesis of EPCs after myocardial infarction exercise. The expression of NRG-1/ErbB4 signaling factor and related proteins in downstream PI3K/AKT signaling pathway were detected, and the level of autocrine NRG-1 in EPCs was detected. Post-MI resistance training, aerobic exercise training, and combined exercise training increased EPC mobilization and proliferation, migration, and tube-forming capacity, promoted myocardial vascular regeneration, improved cardiac function, and reduced infarct size. Exercise training upregulated NRG-1 expression in EPCs, and NRG-1/ErbB4 signaling activated the downstream PI3K/Akt signaling pathway. Moreover, EPCs may have a positive feedback autocrine loop with NRG-1 to improve the function of EPCs and promote vascular repair and regeneration in mice with MI. Exercise training after MI promotes the function of bone marrow-derived EPCs through NRG-1/ErbB4/PI3K/AKT signaling, thus exerting a role in angiogenesis.

The impact of lead and cadmium exposure on subclinical cardiovascular disease (CVD), indicated by elevated high-sensitivity cardiac troponin (hs-cTnT) and N-terminal pro b-type natriuretic peptide (NT-proBNP) remains uncertain. We analyzed data from participants aged 20 and older, without overt CVD, in the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Elevated lead and cadmium levels were defined as 3.5 μg/dL and 1.0 μg/L (inductively coupled plasma mass spectrometry) and 3.8 μg/dL and 0.9 μg/L (atomic absorption spectrometry), respectively. Elevated hs-cTnT was ≥ 19 ng/L, and elevated NT-proBNP was ≥ 125 pg/mL. Multivariate logistic regression estimated the odds ratios (OR) and 95% confidence intervals (CI) for elevated biomarkers. Among 10,197 participants (mean age 48.8 years; 50.3% female), 5.3% had elevated hs-cTnT and 19.4% had elevated NT-proBNP. Elevated blood lead was associated with increased ORs for elevated hs-cTnT (OR 1.45, 95% CI 1.15-1.84) and NT-proBNP (OR 1.66, 95% CI 1.40-1.97). The corresponding ORs (95% CI) for elevated blood cadmium were 1.33 (1.02, 1.74) and 1.39 (1.18, 1.65). The effect of elevated blood lead on NT-proBNP was particularly pronounced among non-Hispanic Blacks (OR [95% CI], 3.26 [2.24, 4.74]) compared to Mexican Americans (1.46 [0.99, 2.17]) and non-Hispanic Whites (1.31 [1.02, 1.68]) and was stronger in individuals with impaired kidney function (OR [95% CI], 2.31 [1.43, 3.75]) compared to those with normal kidney function (1.44 [1.18, 1.75]). This study first reveals the association between lead and cadmium exposure and subclinical CVD, underscoring the need for targeted preventive measures to reduce cardiovascular risk and improve health outcomes.

5-Fluorouracil (5-FU) is a chemotherapeutic that is used to treat solid tumors. However, 5-FU is associated with several side effects, including cardiotoxicity. Considering the importance of the intrinsic cardiac nervous system (ICNS) for the heart and that little is known about effects of 5-FU on this nervous system plexus, the purpose of the present study was to evaluate effects 5-FU at a low dose on the ICNS and oxidative and inflammatory effects in the heart in Wistar rats. The rats were divided into two groups: treated and 5-FU (n = 6/group). The control group received saline only. The treated group received the following clinical doses of 5-FU: 15 mg/kg for 4 consecutive days, followed by 6 mg/kg for 4 days alternated with non-treatment days, and finally 15 mg/kg as the last dose on day 14. On day 15, the rats were euthanized and underwent thoracotomy. The atria were used for histological analysis, and the ventricles were used for biochemical analysis. The results showed an increase in neuronal density and a decrease in ganglionic and neuronal area in the ICNS. Furthermore, tissue inflammation was observed, indicated by an increase in proinflammatory factors and the enzymatic activity of myeloperoxidase and n-acetyl-glucosaminidase. Oxidative stress was also observed, confirmed by a reduction of endogenous antioxidant defenses and the presence of lipoperoxidation. Treatment with 5-FU also caused cardiac atrophy and fibrosis. These findings indicate that cardiotoxicity is present with 5-FU treatment and affects the morphometric aspects of the ICNS.

Atherosclerosis risk is elevated in diabetic patients, but the underlying mechanism such as the involvement of macrophages remains unclear. Here, we investigated the underlying mechanism related to the pro-inflammatory activation of macrophages in the development of diabetic atherosclerosis. Bioinformatics tools were used to analyze the macrophage-related transcriptome differences in patients with atherosclerosis and diabetic mice. LDLR^-/- mice with DDIT4 depletion were generated and fed a Western diet to induce atherosclerosis. DDIT4 expression was elevated in diabetic mice and patients with atherosclerosis. Macrophage proinflammatory factors F4/80, Il-6, and TNFα were reduced in DDIT4^-/-LDLR^-/- mice and necrotic areas were decreased in the aortic root. Atherosclerotic plaque stability was increased in DDIT4^-/-LDLR^-/- mice, as evidenced by increased collagen and smooth muscle cell content. DDIT4, regulated by ETV5, acted on macrophages, affecting lipid accumulation, migration capacity, and pro-inflammatory responses. Knockdown of ETV5 increased expression of DDIT4 and pro-inflammatory factors in macrophages, increased necrotic core area in the aortic root, and decreased stability of atherosclerotic plaques in mice, which was abated by DDIT4 knockdown. The findings provide new insight into how diabetes promotes atherosclerosis and support a model wherein loss of ETV5 sustains transcription of DDIT4 and the pro-inflammatory activation of macrophages.

Dihydromyricetin (Dih), a naturally occurring flavonoid, has been identified to exert a protective effect against ischemia/reperfusion injury. However, the detailed mechanisms remain unclear. Here we investigated the biological role of Dih in preventing hypoxia/reoxygenation (H/R) injury in cardiomyocytes. The results showed that Dih protected cardiomyocytes against H/R-induced apoptosis, as proved by improved cell viability and decreased lactate dehydrogenase (LDH) release, cell apoptosis percentage, and caspase-3/7 activity. H/R-induced oxidative stress in cardiomyocytes was also prevented by Dih with increased activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), and decreased levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Treatment with Dih prevented H/R-induced increase in the activities of myocardial enzymes aspartate aminotransferase (AST), creatine kinase-MB (CK-MB), and creatine kinase (CK). miR-34a expression was upregulated after H/R stimulation, which could be attenuated by Dih pretreatment. Besides, miR-34a overexpression attenuated the protective effects of Dih against H/R-caused increase in apoptosis, oxidative stress, and myocardial enzyme activities. Next, we demonstrated that Notch1 was a target molecule of miR-34a. Notch1 overexpression reversed the role of miR-34a in regulating the cardioprotective effect of Dih on H/R injury. These observations indicated that the cardioprotective effect of Dih against H/R injury was mediated by the miR-34a/Notch1 signaling. Dih may be a candidate agent for improving the clinical efficacy of cardiac ischemia/reperfusion injury treatment.

Pregnancy is a vulnerable time with significant cardiovascular changes that can lead to adverse outcomes, which can extend into the postpartum window. Exposure to emissions from electronic cigarettes (Ecig), commonly known as "vaping," has an adverse impact on cardiovascular function during pregnancy and post-natal life of offspring, but the postpartum effects on maternal health are poorly understood. We used a Sprague Dawley rat model, where pregnant dams are exposed to Ecigs between gestational day (GD)2-GD21 to examine postpartum consequences. Litter and dam health were monitored during the weaning period, and maternal vascular and endocrine function were assessed after weaning. Exposure to Ecig emissions during pregnancy led to fetal losses (i.e., reabsorption in utero) and reduced survival of pups during weaning compared to controls (air-exposed dams). We find that maternal vaping during pregnancy, with or without nicotine (or flavoring) results in maternal vascular and hormonal dysfunction (i.e., reduced prolactin, increased expression of sirtuin 1 deacetylase in the brain). Both 5 and 30W Ecig aerosol exposures resulted in significant impairment of middle cerebral artery reactivity to acetylcholine-mediated dilation (decreasing ~ 22 and ~ 50%, respectively). We also observed an increase in the number of extracellular vesicles (EVs) in plasma from 30-W group that persists up to 3-week postpartum and that these EVs impaired endothelial cell function when applied to in vitro and ex vivo assays. Our data suggest (1) Ecig vaping, even without nicotine or flavorings, during pregnancy alters maternal circulating factors that influence maternal and fetal health, (2) circulating EVs may contribute to the etiology of vascular dysfunction, and (3) that the window for recovery from vascular dysfunction in the dam is likely to be longer than the exposure window.

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.

Ventricular arrhythmias (VAs) are major causes of sudden cardiac death in chronic kidney disease (CKD) patients. Indoxyl sulfate (IS) is one common uremic toxin found in CKD patients. This study investigated whether IS could induce VAs via increasing right ventricular outflow tract (RVOT) arrhythmogenesis. Using conventional microelectrodes and whole-cell patch clamps, we studied the action potentials (APs) and ionic currents of isolated rabbit RVOT tissue preparations and single cardiomyocytes before and after IS (0.1 and 1.0 μM). Calcium fluorescence imaging was performed in RVOT cardiomyocytes treated with and without IS (1.0 μM) to evaluate the calcium transient and the calcium leak. In rabbit RVOT tissues, IS (0.1 and 1.0 μM) attenuated the contractility and shortened the AP durations in a dose-dependent manner. In addition, IS (0.1 and 1.0 μM) enhanced the pro-arrhythmia effects of isoproterenol (ISO, 1.0 μM) and rapid ventricular pacing in RVOT (before versus after ISO, 25% versus 83%, N = 12). In RVOT cardiomyocytes, IS (1.0 μM) significantly decreased the L-type calcium currents but increased the sodium-calcium exchanger and sodium window currents. Cardiomyocytes treated with IS (1.0 μM) had lower calcium transients but higher diastolic calcium and calcium leak than those without IS treatment. Pretreatment with secretoneurin (SN, 30 nM, a potent neuropeptide, suppressing CaMKII) or KN-93 (0.1 μM, a CaMKII inhibitor) prevented IS-induced ionic current changes and arrhythmogenesis. In conclusion, IS modulates RVOT electrophysiology and arrhythmogenesis via enhanced CaMKII activity, which is attenuated by SN, leading to a novel therapeutic target for CKD arrhythmias.

The mortality rate of cardiovascular and cerebrovascular diseases ranks first among all causes. This study elucidated the role and potential mechanism of the NLRC5 gene in atherosclerosis (AS). We enrolled patients (number = 30) diagnosed with AS and healthy volunteers (number = 30) as controls from our hospital. In patients with AS, the levels of serum NLRC5 were up-regulated (Fig. 1A) and positively correlated with CIMT/CRP. In a mouse model of AS, the expression of serum NLRC5 mRNA was increased at 6 or 12 weeks after inducing AS. The expression of NLRC5 protein was found to be elevated in a mouse model of AS. The inhibition of NLRC5 reduced development of AS in ApoE^-/- Mice. Reducing NLRC5 inhibited the polarization of M2 macrophages and shifted macrophages towards proinflammatory M1 phenotype. STAT3 was identified as a target of NLRC5, with NLRC5 protein expression shown to reduce STAT3 ubiquitination. Methylation promoted NLRC5 DNA stability in vitro model of AS. Sh-NLRC5 increased M1/M2 macrophage ratio, foam cell formation and ox-LDL uptake. STAT3 reduced the effects of sh-NLRC5-mediated M1/M2 macrophage ratio in model of AS. These data confirmed that NLRC5 in macrophages promotes atherosclerosis in acute coronary syndrome by regulating STAT3 expression. This suggests that NLRC5 could be a potential target for the treatment of premature AS.

Although 5-fluorouracil (5-FU) is widely utilized in cancer treatment, its side effects, including cardiotoxicity, limit its use. Taxifolin (TAX) is a bioactive anti-inflammatory and antioxidant flavonoid. This study aimed to elucidate the protective effect of TAX against 5-FU-induced cardiac injury in male mice. Mice were treated with TAX (25 and 50 mg/kg, orally) for 10 days and a single dose of 150 mg/kg 5-FU at day 8. Mice intoxicated with 5-FU showed increased creatine kinase-MB and lactate dehydrogenase activities and troponin I levels, with multiple cardiac histopathological changes. They also showed a significant increase in cardiac malondialdehyde (MDA) and nitric oxide (NO) and decreases in myocardial reduced glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities (P < 0.001). Pretreatment of 5-FU-injected mice with TAX suppressed cardiac injury, decreased MDA and NO contents (P < 0.001), and boosted antioxidant defenses in the myocardium. Moreover, TAX attenuated cardiac inflammatory response, as evidenced by the decreased expression levels of cardiac NF-κB p65, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines (P < 0.001). Largely, TAX ameliorated the decrease in Bcl-2 expression and the increase in BAX and caspase-3 in the heart. It also restored the cardiac Sirt1/Nrf2/HO-1 signaling pathway. In conclusion, TAX showed significant cardioprotective effects on 5-FU-induced cardiac injury and might represent a promising adjuvant in preventing cardiac injury associated with oxidative stress and inflammation.