Cardiovascular Toxicology最新文献

Vascular hyporeactivity is one of the the leading causes of death in sepsis. Ubiquitylation regulates the turnover of different cellular proteins; however, its role in controlling vascular dysfunction in sepsis is largely unknown. Herein, we aimed to evaluate the role of Cullin-3-RING ubiquitin ligase in regulating vascular contractile protein (RhoA) homeostasis and thereby regulating sepsis-induced vascular dysfunction. Sepsis was induced by caecal ligation and puncture (CLP) in mice. Cullin neddylation inhibitor (MLN4924) was evaluated for its possible therapeutic use in experimental sepsis in mice. Sepsis significantly impaired vascular RhoA/ROCK signaling as corroborated by marked increase in vasorelaxant response to Y-27632 (a Rho kinase inhibitor) which was found to be mediated by iNOS/NO/sGC pathway. Further, a significant down-expression of vascular RhoA/ROCK in septic mice was accompanied with increase in the protein expression of neddylated cullin3. Additionally, the silencing of cullin3 in vascular smooth muscle cells resulted in increase in the protein expression of RhoA. Treatment of septic mice with MLN4924, a neddylation inhibitor, significantly improved the vascular reactivity as evidenced by reduction in relaxant response to Y-27632, increase in protein level of RhoA in aorta with concomitant restoration of the contractile response to nor-adrenaline. However, MLN4924 treated mice showed higher bacterial load in blood, peritoneal lavage, lungs and spleen of septic mice. Taken together, sepsis-induced increase in cullin3 mediated degradation of RhoA possibly contributes to the vascular hyporeactivity. Thus, inhibition of vasculo-specific cullin neddylation by MLN4924 seems a potential therapeutic target for treating sepsis-induced vascular dysfunctions.

Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, offers vascular protection beyond its glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). As endothelial dysfunction is a key initiator of vascular disease, understanding the precise regulatory mechanisms of EMPA in diabetic vascular complications is of great interest. In this study, we evaluated the therapeutic potential of EMPA in promoting blood flow recovery and revascularization under diabetic conditions using a hindlimb ischemia (HLI) model in db/db mice. We also investigated the effects of EMPA on the angiogenic function of endothelial cells exposed to high glucose and palmitate (HG/PA) conditions, mimicking the metabolic milieu of T2DM. The results demonstrated that EMPA significantly improved blood perfusion recovery in ischemic limbs, concomitant with enhanced angiogenesis and arteriogenesis in the ischemic gastrocnemius muscle. At the cellular level, EMPA effectively preserved endothelial function by mitigating HG/PA-induced impairments in cell migration and tube formation. Notably, EMPA treatment substantially ameliorated diabetes-induced oxidative stress in both muscle tissues and endothelial cells. Mechanistic studies revealed that EMPA upregulated antioxidant gene expression through SETD2-mediated pathways, thereby restoring endothelial angiogenic function under diabetic conditions. Taken together, these findings highlight that EMPA's therapeutic potential in diabetic HLI by attenuating oxidative stress and enhancing endothelial function.

Mercury exposure triggers localized oxidative stress, playing a central role in its detrimental effects, because toxic levels of ROS induce lipid peroxidation, promote protein oxidation and nitration, and nucleic acid oxidation and damage. Egg white hydrolysate (EWH), a functional food, is a protein extract that has promising capabilities against metal-induced cardiovascular damage. However, its potential in preventing the acute effects of mercury exposure remains unexplored. This study evaluated the preventive efficacy of 3 days, a short-term EWH treatment against the subsequent acute exposure to HgCl₂ in isolated left ventricle papillary muscles. Male Wistar rats were divided into four groups: Control, EWH, HgCl₂ and EWH + HgCl₂. Animals received filtered water or EWH (1 g/kg/day) via oral gavage for 3 days as pre-treatment. Subsequently, papillary muscles were isolated, and then HgCl₂ and EWH + HgCl₂ groups were exposed to 6 nM HgCl₂ for 60 min. Results revealed that acute HgCl₂ exposure impaired force generation, positive and negative time derivatives of force, indicating contractile dysfunction. Notably, these effects were absent in the EWH + HgCl₂ group. Furthermore, HgCl₂ exposure depressed post-rest potentiation, inotropic response protocols to calcium and isoproterenol while the EWH + HgCl₂ group exhibited comparable responses to the control group. Besides that, the increase in ROS levels induced by HgCl₂ in vitro was prevented by EWH pre-treatment. In conclusion, EWH demonstrated a cardioprotective effect by preserving contractile function, maintaining physiological inotropic responses, and preventing ROS accumulation with a remarkably brief 3-day pre-treatment period, highlighting its potential against the deleterious effects of acute mercury exposure, particularly in unavoidable or unpredictable exposures.

Immunotherapy is revolutionizing the treatment of cancer and other conditions. However, it also precipitates a loss of self-tolerance and causes immune-related adverse events (irAEs). We provide a narrative synthesis of the scopes and methods of immunotherapy and mechanisms, clinical presentation, and diagnostic considerations of cardiovascular irAEs while providing real-world examples and perspectives. Recent real-world cases and emerging evidence suggest myocarditis is the most common and potentially fatal cardiovascular irAE, often presenting with symptoms such as shortness of breath or chest pain within weeks of therapy initiation. Other cardiotoxic effects include arrhythmias such as tachyarrhythmias or conduction blocks, heart failure, takotsubo cardiomyopathy, and pericardial disease, sometimes with pericardial effusion. These events can be severe, requiring prompt recognition and intervention to avoid deterioration. Diagnosis typically involves surveillance, a high index of suspicion, biomarker elevations, imaging modalities, cardiac magnetic resonance, and in select cases, endomyocardial biopsy. Early cessation of immunotherapy and high-dose corticosteroids frequently help stabilize acutely ill patients with additional immunomodulators such as intravenous immunoglobulin or abatacept considered in steroid-refractory cases. Clinicians are urged to adopt a multidisciplinary approach involving close cardiology collaboration for baseline risk evaluation, structured surveillance, and cautious rechallenge decisions. Despite these challenges, immunotherapy remains vital for the management of many malignancies. Ongoing research into targeted immunomodulation, refined imaging protocols, and genetic profiling may enhance clinical outcomes by enabling prevention, earlier detection and safer management of cardiovascular irAEs.

Monoamine oxidase (MAO) helps regulate catecholaminergic signaling via metabolism of neurotransmitters epinephrine, norepinephrine, and dopamine-in turn producing the metabolites hydrogen peroxide (H₂O₂), ammonia (NH₄⁺), and corresponding catecholaldehydes. While MAO has been a key facet of neuroscience and mood disorder research for > 60 years, MAO-generated metabolites have been largely overlooked until recently when reports have begun to illustrate the reactivity of these metabolites and their pathogenic contributions to disease (e.g., inflammation, fibrosis, cell death). These findings have extended MAO's biological relevance beyond the brain and, most notably, to the heart, where a large and growing body of literature clearly indicates a pathophysiologic role for MAO-mediated catecholamine metabolism in heart disease. Herein, we discuss the evidence connecting MAO to various cardiac injuries and disorders, as well as describe the known cardiotoxicity associated with MAO's reactive metabolites, specifically in connection to cardiac pathophysiology. Potential therapeutic strategies for targeting MAO and its metabolites to prevent and treat heart disease are also discussed, and important knowledge gaps highlighted.

Among the drugs used for insomnia, the use of benzodiazepine and non-benzodiazepine hypnotics is correlated to the occurrence of cardiac arrhythmia. Conversely, melatonin receptor agonists may exert cardioprotective effects. Therefore, in the present study, we investigated the association between the use of melatonin receptor agonists and the occurrence of cardiac arrhythmia using the Food and Drug Administration Adverse Event Reporting System (FAERS). Eligible patients are registered in FAERS. The targeted drugs were melatonin receptor agonists and benzodiazepine receptor agonists (BZRAs). The target disease was cardiac arrhythmia, and data for the disease were extracted from the Medical Dictionary for Regulatory Activities (MedDRA) 27.1; Standardized MedDRA Query (SMQ). The reporting odds ratio (ROR) was calculated in the study. The results showed that melatonin receptor agonists were negatively correlated with all cardiac arrhythmia-related SMQs. The RORs for each SMQ were as follows: "cardiac arrhythmias" (ROR: 0.47, 95%CI: 0.41-0.54), "bradyarrhythmias" (ROR: 0.20, 95%CI: 0.10-0.40), "tachyarrhythmias" (ROR: 0.21, 95%CI: 0.13-0.33), "supraventricular tachyarrhythmias" (ROR: 0.24, 95%CI: 0.14-0.41), "ventricular tachyarrhythmias" (ROR: 0.05, 95%CI: 0.01-0.33), and "TdP" (ROR: 0.32, 95%CI: 0.25-0.41). Conversely, BZRAs were positively correlated with cardiac arrhythmia-related SMQs. Overall, the present results suggest that compared with BZRAs, melatonin receptor agonist usage is weakly associated with cardiac arrhythmia.

Metabolic Syndrome (MetS) is a major public health problem that has imposed enormous socio-economic burdens in most countries and regions. This study aims to investigate the association of urinary Zinc (Zn) with the risk of MetS and its components among the Bouyei ethnic group, and the role of liver enzymes as mediators in this relationship. Zn concentrations in the urine of 5033 participants were measured by inductively coupled plasma mass spectrometry. An automatic biochemical analyzer was used to detect blood biochemical indexes. Binary logistic regression showed that compared with Q1, the OR (95% CI) for MetS, hyperglycemia, and elevated triglyceride in Q4 were 2.22 (1.69-2.92), 2.35 (1.73-3.18), and 1.38 (1.15-1.66), respectively. The results of the mediation analysis showed that liver enzyme may act as a partial mediator of the association between urinary Zn and MetS, with the mediating effect of gamma glutamyl transferase (GGT) accounting for 11.60% of the total effect. In conclusion, we found that urinary Zn was positively associated with MetS and its components among the Bouyei ethnic group in Guizhou Province. GGT appeared to play a partial mediating role between urinary Zn and the risk of MetS.

Ferroptosis occurs after myocardial ischemia-reperfusion (I/R) injury. Long non-coding RNA (lncRNA) AK020546 possesses the effect of protecting the myocardium from I/R injury; however, the underlying mechanisms remain not fully understood. This study aimed to investigate the effect of AK020546 on ferroptosis in cardiomyocytes and underlying molecular mechanisms. Hypoxia/reoxygenation (H/R) was used to induce H9C2 injury, and an I/R rat model was generated. Ferroptosis was evaluated by detecting lipid reactive oxygen species, Fe²⁺, glutathione, and malondialdehyde levels. The N(6)-methyladenosine (m6A) methylation of Mst1 was assessed by RNA binding protein immunoprecipitation (RIP), methylated-RIP, luciferase reporter assay, and RNA stability assay. The results showed that AK020546 inhibited H/R-induced ferroptosis. It also decreased Mst1 expression through binding with METTL14. Moreover, METTL14 promoted m6A methylation of Mst1, thereby enhancing its stability. METTL14 and Mst1 were involved in AK020546-mediated ferroptosis. Besides, AK020546 alleviated myocardial damage in I/R rats. In conclusion, the AK020546/METTL14/m6A-Mst1 axis protects against myocardial I/R injury by suppressing cardiomyocyte ferroptosis, suggesting a promising target for myocardial I/R injury.

It is known that COVID-19 patients may experience endothelial cell inflammation, apoptosis, dysfunction, and systemic coagulation disorders. In CABG operations, graft patency plays a crucial role in survival and morbidity. Thrombosis and endothelial cell inflammation in grafts can pose challenges for CABG candidates with a history of COVID-19. This study aimed to evaluate the vasculitic effects of a history of COVID-19 among CABG patients. A total of 94 consecutive patients, including 34 with a history of COVID-19 and 60 without, who were scheduled for CABG at our clinic, were included in the study after informed consent was obtained. Patients with a history of COVID-19 underwent surgery at least 4 weeks after the recovery of infection. Thromboembolic events were monitored throughout the hospital stay, and vascular grafts obtained during surgery were pathologically evaluated for signs of vasculitis and inflammation. All COVID-19 (n = 34) cases were mild. Statistical analysis revealed no significant difference between the groups regarding vein thrombosis/thrombophlebitis (p = 0.626). Additionally, pathological evaluation showed no signs of vasculitis or inflammation. There were also no significant differences in postoperative mortality and morbidity between the two groups (p > 0.05). Based on our findings, undergoing CABG surgery after a four-week recovery period appears to be safe for patients with a history of mild COVID-19, at least in terms of early postoperative vascular outcomes.

Plasticizers, particularly bisphenols and phthalates, are prevalent additives in plastic products that enhance durability, shape, and flexibility. However, bisphenols and phthalates have been associated with adverse health effects. Recent studies linked these plasticizers to cardiovascular diseases, implicating the Renin-Angiotensin System (RAS) as a potential mediator of these effects. This review explores the relationship between plasticizer exposure and RAS modulation, focusing on cardiovascular outcomes. A systematic search was conducted in PubMed up to November 2024 according to the PRISMA guideline. The words used in this research were bisphenol, phthalates, angiotensin-converting enzyme, angiotensin II type 1 receptor, angiotensin, angiotensinogen, renin-angiotensin system, heart, cardio* (cardiovascular terms), hypertension, and blood pressure to find all relevant articles published. Thirty-one studies were screened based on inclusion and exclusion criteria, and thirteen articles were included in this systematic review. In different experimental models, several cardiovascular effects were associated with exposure to different doses of Bisphenol A (BPA) and phthalates due to the overactivation of the classical axis of the RAS. BPA exposure led to hypertension, vascular cell proliferation, and oxidative stress, and aggravated hypertensive and malnourishment conditions. In animal models, phthalates increased blood pressure, vascular thickening, and cardiac hypertrophy. These effects were partially reduced by ACE inhibition, highlighting the critical role of the RAS in plasticizer-induced cardiovascular outcomes (hypertension, smooth muscle cell proliferation, cardiac hypertrophy and fibrosis, and cardiovascular inflammation). The role of the counterregulatory axis of the RAS and the effects of emerging plasticizer analogs on cardiovascular health should be addressed by future investigations.