Cardiovascular Toxicology最新文献

Sepsis causes systemic organ and tissue dysfunction, among which myocardial injury has become an urgent clinical problem. Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that plays an important role in cellular activities. In this study, we investigated the regulatory role of HIPK2 regarding the level of ferroptosis in septic myocardial injury. Trends in ferroptosis and HIPK2 expression were observed over time in a mouse model of sepsis in which cecum ligation perforation was performed. Lipopolysaccharide (LPS)-treated H9c2 cells were used to establish the experimental model, and both HIPK2 overexpression and HIPK2 knockdown H9c2 cells were used to measure the levels of inflammatory markers and ferroptosis-associated proteins. The experimental data revealed that the model mice exhibited greater degrees of myocardial injury, cardiac dysfunction, and ferroptosis compared with normal sham-operated mice, and these effects progressively worsened with increasing duration of sepsis. HIPK2 expression progressively decreased with a prolonged duration of sepsis. Compared with the control H9c2 cells, the LPS-treated H9c2 cells exhibited decreased cell viability and increased cytotoxicity, ferroptosis, and inflammatory responses. HIPK2 overexpression downregulated the levels of inflammatory and ferroptosis mediators, whereas HIPK2 knockdown demonstrated the opposite effects. HIPK2 may play a protective role against septic myocardial injury by modulating ferroptosis.

This study investigated blood selenium (Se) levels in chronic heart failure (CHF) patients and their correlation with cardiac function, followed by a meta-analysis of Se supplementation efficacy. We enrolled 191 CHF patients, measuring blood Se via 2,3-diaminonaphthalene fluorometry. Data were analyzed using SPSS 25.0 and GraphPad Prism 8.0. A systematic review of randomized trials on Se supplementation for CHF was conducted (RevMan 5.3 and Stata 16.0). CHF patients exhibited significantly lower blood Se (P_2.5-P_97.5: 55.12-81.38 μg/L; median: 67.04 μg/L) versus healthy controls. Lower Se levels correlated with obesity (P = 0.001), rural residence (P = 0.009), hypertension (P = 0.038), and advanced cardiac dysfunction (class III/IV vs. I/II, P = 0.002). Se inversely correlated with CRP (r =  - 0.22, P = 0.026). Meta-analysis revealed that Se supplementation reduced systolic blood pressure (P = 0.04) but increased LVESV (SMD = 0.21, P = 0.04). CHF patients frequently exhibit Se deficiency, linked to BMI, cardiac function, and inflammation. Hypertension and low Se may exacerbate cardiac dysfunction, while controlled Se supplementation could improve outcomes.

Lead poisoning remains a significant threat to both human and animal health, with cardiovascular dysfunction being one of its primary adverse effects. This study aimed to investigate the function of the right atrium and right ventricle in 12-month-old male rats exposed to 5.5, 11, and 22.88 mg/kg body weight of lead acetate, injected intraperitoneally three times a week for six weeks. Lead exposure resulted in a reduction in blood pressure (11 mg/kg b.w.) and QRS amplitude, and a lowering of the isoelectric line. Lead exposure led to a dose-dependent shift in the myosin heavy chain (MHC) ratio toward the slower β-MHC isoform in the right ventricle, whereas no changes were detected in the right atrium. We observed a dose-dependent increase in myosin regulatory light chain phosphorylation in the right ventricle and a decrease in the right atrium. In the atria, both active and passive tensions were reduced, while no significant alterations were found in the right ventricle. However, a dose-dependent slowing of the action potential was found in both atrial and ventricular myocardium. Both the right atrium and right ventricle demonstrated responses to lead exposure; however, there was a mismatch between the alterations observed in atrial and ventricular parameters. These findings suggest that the atrial and ventricular myocardium adapt differently to lead exposure, with their responses varying depending on the specific dosage of lead consumed.

Preeclampsia is a multisystemic cardiovascular pregnancy complication that endangers the lives of both mother and child. Its prevalence disproportionately burdens women of different races and ethnicities nationwide. Specifically, Hispanic women experience higher rates of preeclampsia compared to Non-Hispanic White women; however, the explanation for this phenomenon is still elusive. To decipher these disparate rates, environmental factors that the Hispanic community is excessively exposed to may need to be considered. Environmental toxicants such as particulate matter, heavy metals, phthalates, as well as microplastics and nanoplastics are ubiquitous within the Hispanic environment. From places of employment to in the home, the role of chronic toxicant exposure in Hispanic women may begin to explain the gap in the prevalence of preeclampsia development. To understand the relationship between toxicant exposure and preeclampsia, we explored epigenetic concepts. With the capacity to respond to the environment in a heritable and reversible manner, epigenetics changes the expression of genes and proteins while leaving the DNA sequence intact. Epigenetic modifications can be dysregulated upon toxicant exposure and can potentially lead to the development of preeclampsia. Here, in this review, we propose the potential epigenetic links through which Hispanic women's disproportionate environmental exposure to toxicants can be conducive to preeclampsia development.

The relevance of NOS3 common polymorphisms to coronary heart disease (CHD) risk is inconsistent among different studies, and little is known about the contribution of the genetic variants to the disease development across ancestries and age groups. To address this, we performed a comprehensive meta-analysis stratified by age and ancestry, including 123 eligible studies (29,040 cases and 26,694 controls). Random- or fixed-effects models were applied, based on heterogeneity statistics, to assess the association between the selected polymorphisms (rs1799983 and rs2070744) and CHD risk under various genetic models; p-values were corrected for multiple comparisons. Our findings indicate that the effect of both polymorphisms on the CHD risk varies across ancestries and age groups. In individuals under 55 years, rs1799983, but not rs2070744, showed a marginally significant association with CHD risk in the pooled analysis. However, neither variant appears to be involved in CHD development within any tested ancestry, including East Asian, European, Greater Middle Eastern, and South Asian populations. In individuals over 55 years, rs1799983 was significantly associated with an increased risk of CHD in East Asian, European, and Greater Middle Eastern populations, while rs2070744 contributed to CHD risk in East Asians and Europeans. Among all ancestries, both polymorphisms showed the strongest associations with the disease risk in East Asians, with no significant association observed in the American population. This meta-analysis advances our understanding of the impact of well-known NOS3 variants on CHD incidence across diverse age and ancestry groups. It proposes that the genetic risk of CHD associated with rs1799983 and rs2070744 might be more prominent in older individuals with prolonged environmental exposures. Such insights are critical for developing genetic screening panels to efficiently identify individuals who are genetically at high risk for CHD development.

Atherosclerosis (AS) is a fundamental pathological process underlying cardiovascular disease (CVD), which begins with dysfunction in the endothelial system resulting from damage to vascular endothelial cells. Our research demonstrates that the deubiquitinating enzyme USP5 is upregulated in endothelial cells of AS plaques. In vitro, USP5 knockdown enhanced cell viability, whereas attenuated ox-LDL-induced apoptosis, oxidative stress, inflammation, and endothelial dysfunction in HUVECs. In vivo studies in a mouse model of atherosclerosis showed that USP5 inhibition significantly reduced plaque formation, collagen deposition, and inflammatory cell infiltration. Protein mass spectrometry analysis and immunoprecipitation assays show that USP5 interacts with programmed cell death 4 (PDCD4). PDCD4 overexpression rescues USP5 knockdown effects on HUVECs exposed to ox-LDL. This study elucidates the biological functions of the USP5/PDCD4 axis in the injury of cells of the vascular endothelium during AS and suggests that targeting this axis could offer a potential therapeutic strategy for atherosclerosis.

The dog with chronic atrioventricular block (CAVB) combines a number of risk factors associated with Torsade de Pointes (TdP) arrhythmias. Nevertheless, approximately 33% of the animals are resistant to dofetilide-induced TdP arrhythmia. Of a group of 78 experimentally identical CAVB dogs, we compared TdP inducible vs. non-inducible animals for a set of basic, and cardiac electrical and mechanical parameters. Body weight, but not sex or age, is associated with TdP inducibility. Of the cardiac parameters, longer ventricular repolarization duration and increased contractility at baseline are associated with dofetilide-induced TdP arrhythmias. Differences in cardiac parameters disappeared upon dofetilide infusion. We discuss that prolonged repolarization and increased contractility may be early indications of calcium-mediated early after depolarization that may develop into TdP arrhythmias.

This study aims to evaluate the potential role of statins in preventing doxorubicin-induced cardiotoxicity. With the rising number of cancer survivors and the persistent use of doxorubicin in treatment protocols, there is an urgent need for effective cardioprotective strategies to mitigate long-term cardiovascular complications. Statins, widely used for cardiovascular disease prevention, offer a promising repurposing opportunity due to their pleiotropic effects. A comprehensive review of existing animal and clinical studies was conducted to assess the cardioprotective effects of statins. Key mechanisms such as reduction of oxidative stress, inflammation, and apoptosis were examined, alongside current clinical evidence evaluating their use in patients receiving doxorubicin. Preclinical studies consistently demonstrate that statins significantly reduce doxorubicin-induced cardiotoxicity by modulating multiple cellular pathways involved in oxidative stress, inflammation, and programmed cell death. These findings highlight statins' multifaceted mechanisms of action in protecting cardiac tissue. Numerous observational studies have shown that statin therapy may reduce the incidence and severity of doxorubicin-induced cardiotoxicity, reflected by less decline in left ventricular ejection fraction and a lower risk of heart failure in those receiving statins, but results from randomized controlled trials remain inconsistent. Given the growing burden of cancer therapy-related cardiovascular disease and the established safety profile of statins, further large-scale clinical trials are warranted to confirm their protective role, determine optimal dosing strategies, and facilitate integration into oncology practice. Establishing their utility could improve long-term outcomes for cancer patients vulnerable to cardiotoxicity.

Hypertension is characterized by chronic inflammation. Anatabine, a natural alkaloid with anti-inflammatory properties, has demonstrated potential in regulating inflammatory pathways. However, its impact on cardiovascular activity in the context of hypertension remains unclear. The aim of this study was to explore the effects of anatabine on cardiovascular activity in hypertensive rats, with a specific focus on the underlying mechanisms related to inflammation and oxidative stress, particularly the role of NLRP3 inflammasome and pyroptosis in the PVN. Fecal samples were collected from male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, followed by untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS). Anatabine (ANT) was identified as enriched in WKY while lacking in SHR and thus was subcutaneously administered via mini-pump (0.014 mg/kg/min) in SHR or WKY rats for 12 weeks. Systolic blood pressure was recorded weekly. In vitro, microglia (HMC3) were divided into control, angiotensin II (Ang II), Ang II + anatabine, and Ang II + anatabine + PapRIV (Pap, NF-κB activator) groups. High blood pressure significantly triggered nucleotide-binding domain, leucine-rich-containing family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation (ASC, Caspase-1, and NLRP3), and pyroptosis (GSDMD) in the hypothalamic paraventricular nucleus (PVN), which evoked massive inflammatory cytokine production (IL-1β, TNF-α, IL-18, and MCP-1) and oxidative stress responses (Cu/Zn-SOD activity, GSH-PX, and MDA) in the SHR group. Notably, anatabine not only prevented cardiac structural remodeling and attenuated sympathetic activation but also reduced the inflammatory reaction from the NF-κB activity, NLRP3-dependent inflammasome and pyroptosis, and decreased reactive oxygen species (ROS) overproduction in the PVN of hypertensive rats. In vitro, microglia stimulated inflammation after adding Ang II; oxidative stress responses were activated, while the inflammasome compounds and cytokines were overexpressed. The anatabine inhibited NF-κB activity, NLRP3/caspase-1-dependent pyroptosis and oxidative stress in Ang II-induced microglia. Conversely, those responses were aggravated after the NF-κB activator in HMC3. Chronic hypertension activates the NLRP3 inflammasome and pyroptosis-driven inflammatory responses, leading to oxidative stress in the PVN. Sustained administration of anatabine reached the PVN and suppressed the NF-κB/NLRP3/caspase-1-dependent pyroptosis pathway in microglia, reducing excessive ROS generation in the PVN, thereby effectively reducing sympathetic drive, attenuating blood pressure, and preventing cardiac structural remodeling in the process of hypertension. These findings suggest anatabine as a promising therapeutic agent for managing hypertension-related chronic inflammation.