Cardiovascular Toxicology最新文献

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.

Many 1990-1991 Gulf War Veterans (GWVs) were exposed to toxicants and environmental hazards during deployment, including oil well fire smoke, chemical/biological agents, pyridostigmine bromide (PB) pills, and pesticides. Multiple constituents of smoke are associated with increased risk for atherosclerotic cardiovascular diseases (ASCVD), and other toxic exposures have been associated with autonomic and lipid dysfunction. We used data from the Gulf War Era Cohort and Biorepository Study of veterans deployed to Gulf War in 1990-1991 (n = 942). We evaluated the association of deployment exposures (no, yes (1-6 days), (7-30 days), (31 + days), and not sure) with clinical risk factors (hypertension, diabetes, high cholesterol) and ASCVD using multivariable logistic regression. We adjusted for all clinical risk factors in the models to test the association of military exposures and ASCVD. We found that 7-30 days exposure to oil well fire smoke (OR: 2.95, CI: 1.40, 6.19), PB pills (OR: 2.37, CI: 1.06, 5.32), and chemical/biological agents (OR: 3.60, CI: 1.04, 12.51) were associated with ASCVD. Exposure to chemical/biological agents for 7-30 days was also associated with hypertension (OR: 4.18, CI: 1.48, 11.86) and for 31 + days was associated with ASCVD (OR: 4.24, CI:1.20, 14.94). The associations between oil well fire smoke and chemical/biological agents with ASCVD remained significant in models adjusting for clinical risk factors. For GWVs, exposure to oil well fire smoke, chemical/biological agents, and PB pills were associated with ASCVD. These exposures may represent population-specific risk enhancers for ASCVD and may be considered in individualized clinical risk assessment.

Gonadotropin-releasing hormone (GnRH) therapy, a cornerstone in the treatment of various oncological and reproductive conditions, has been increasingly associated with significant cardiovascular risks, particularly when administered long-term. This review examines the complex relationship between GnRH therapy, metabolic dysregulation, and cardiotoxicity, with a focus on the mechanisms driving these cardiovascular outcomes. Prolonged GnRH suppression induces a spectrum of metabolic disturbances, including insulin resistance, dyslipidemia, and obesity, all of which elevate the risk of cardiovascular events such as hypertension, myocardial infarction, and stroke. These risks are further influenced by sex-specific differences and pre-existing cardiovascular conditions, necessitating tailored therapeutic strategies. The review highlights the urgent need for comprehensive monitoring and early intervention in patients undergoing GnRH treatment, with a particular emphasis on personalized care approaches. Additionally, we explore both pharmacological and non-pharmacological interventions aimed at mitigating these risks, including the potential of next-generation GnRH modulators and combination therapies. The need for future research is underscored, particularly in understanding the molecular and cellular mechanisms underlying cardiovascular toxicity, identifying predictive biomarkers, and developing safer therapeutic alternatives. This review provides a comprehensive framework for clinicians and researchers working to optimize the benefits of GnRH therapy while minimizing its cardiovascular burden, ultimately improving patient outcomes across various clinical settings.

Cardiotoxicity is a recognized adverse effect associated with anti-HER2 therapies. The Trastuzumab-mediated cardiac dysfunction is not dose-dependent and lacks ultrastructural changes, allowing potential recovery after a few months. There is no consensus on the management of patients who develop cardiotoxicity. This meta-analysis aims to assess the safety of the permissive cardiotoxicity of Trastuzumab in patients with breast cancer. We searched PubMed, Cochrane Library, and Embase up to October 2023 for retrospective or prospective studies that investigated the safety of Trastuzumab in patients with breast cancer who continued Trastuzumab therapy after asymptomatic ejection fraction (EF) decline. We conducted a pooled meta-analysis for the subsequent cardiac events, cardiac mortality, and all-cause mortality. We assessed the quality of included studies using the Newcastle-Ottawa Scale and ROBIN-1 tool. A total of eight cohort studies (six retrospective and two prospective), comprising 222 patients, were found eligible and were included in our analysis. The pooled incidence of cardiac events, cardiac-related mortality, and all-cause mortality was 18% (95% CI 13% to 24%), 5% (95% CI 2% to 10%), and 8% (95% CI 2% to 28%), respectively. The incidence of symptomatic or severe cardiac events was lower in those who received cardioprotective medications concomitant with Trastuzumab. Most patients received either angiotensin-converting-enzyme inhibitors, beta-blockers, or a combination of both. Continuation of planned Trastuzumab therapy with concomitant use of cardioprotective medications can be a safe and effective approach for breast cancer control in patients with asymptomatic EF decline.

Air pollution, a global health concern, is linked to atherosclerosis through epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNA regulation. Long-term exposure to air pollution such as particulate matter 2.5 (PM 2.5), polycyclic aromatic hydrocarbons (PAHs), and heavy metals can induce alterations in DNA methylation patterns, especially in genes regulating inflammation and cholesterol metabolism, contributing to atherosclerosis development. DNA methylation plays a fundamental role in regulating gene expression by silencing or activating genes involved in endothelial dysfunction, inflammation, and lipid metabolism, all of which contribute to atherosclerosis progression. Moreover, it explores the influence of air pollution on histone modifications, emphasizing their role in pathways critical to atherosclerotic progression. Histone modifications, such as acetylation and methylation, alter chromatin structure and gene accessibility, impacting key signaling pathways related to vascular inflammation and plaque formation. It explores the interconnection between air pollution and non-coding RNA (ncRNA) modifications, shedding light on the significance of miRNAs and lncRNAs as potential biomarkers indicative of cardiovascular susceptibility triggered by exposure to particulate matter (PM). Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), modulate post-transcriptional gene regulation, influencing inflammatory responses, oxidative stress, and endothelial function in atherosclerosis. Understanding these epigenetic changes is vital for developing strategies to mitigate air pollution's impact on cardiovascular health.