Cardiovascular Toxicology最新文献

Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM_2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM_2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM_2.5 at 250 µg/m³ for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM_2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM_2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α.

Doxorubicin (Dox) has been limited in clinical application due to its cardiac toxicity that varies with the dose. This study aimed to explore how Rhein modulates Dox-induced myocardial toxicity. The general condition and echocardiographic changes of mice were observed to evaluate cardiac function and structure, with myocardial cell injury and apoptosis checked by TUNEL and HE staining. The ELISA assessed markers of myocardial damage and inflammation. The TCMSP and SwissTargetPrediction databases were used to retrieve Rhein's targets while GeneCards was used to find genes related to Dox-induced myocardial injury. Intersection genes were analyzed by Protein-Protein Interaction Networks. The core network genes underwent GO and KEGG enrichment analysis using R software. Western blot was used to detect protein expression. Compared to the Dox group, there was no remarkable difference in heart mass /body mass ratio in the Rhein+Dox group. However, heart mass/tibia length increased. Mice in the Rhein+Dox group had significantly increased LVEF, LVPWs, and LVFS compared to those in the Dox group. Myocardial cell damage, inflammation, and apoptosis significantly reduced in the Rhein+Dox group compared to the model group. Eleven core network genes were selected. Further, Rhein+Dox group showed significantly downregulated expression of p38/p-p38, HSP90AA1, c-Jun/p-c-Jun, c-Fos/p-c-Fos, Bax, and cleaved-caspase-3/caspase-3 while Bcl-2 expression significantly upregulated compared to the Dox group. The study suggests that Rhein mediates cardioprotection against Dox-induced myocardial injury, at least partly, by influencing multiple core genes in the MAPK signaling pathway to inhibit myocardial cell apoptosis.

Cardiovascular disease is the deadly disease that can result in sudden death, and inflammation plays an important role in its onset and progression. High mobility group box 1 (HMGB1) is a nuclear protein that regulates transcription, DNA replication, repair, and nucleosome assembly. HMGB1 is released passively by necrotic tissues and actively secreted by stressed cells. Extracellular HMGB1 functions as a damage associated molecular patterns molecule, producing numerous redox forms that induce a range of cellular responses by binding to distinct receptors and interactors, including tissue inflammation and regeneration. Extracellular HMGB1 inhibition reduces inflammation and is protective in experimental models of myocardial ischemia/reperfusion damage, myocarditis, cardiomyopathies caused by mechanical stress, diabetes, bacterial infection, or chemotherapeutic drugs. HMGB1 administration following a myocardial infarction followed by permanent coronary artery ligation improves cardiac function by stimulating tissue regeneration. HMGB1 inhibits contractility and produces hypertrophy and death in cardiomyocytes, while also stimulating cardiac fibroblast activity and promoting cardiac stem cell proliferation and differentiation. Maintaining normal nuclear HMGB1 levels, interestingly, protects cardiomyocytes from apoptosis by limiting DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac injury. Finally, elevated levels of circulating HMGB1 have been linked to human heart disease. As a result, following cardiac damage, HMGB1 elicits both detrimental and helpful responses, which may be due to the formation and stability of the various redox forms, the particular activities of which in this context are mostly unknown. This review covers recent findings in HMGB1 biology and cardiac dysfunction.

To uncover the possible role of TRAF3IP3 in the progression of myocardial infarction (MI), clarify its role in mitophagy and mitochondrial function, and explore the underlying mechanism. GEO chip analysis, RT-qPCR, and LDH release assay were used to detect the expression of TRAF3IP3 in tissues and cells and its effects on cell damage. Immunostaining and ATP product assays were performed to examine the effects of TRAF3IP3 on mitochondrial function. Co-IP, CHX assays, Immunoblot and Immunostaining assays were conducted to determine the effects of TRAF3IP3 on mitophagy. TRAF3IP3 was highly expressed in IR rats and HR-induced H9C2 cells. TRAF3IP3 knockdown can alleviate H/R-induced H9C2 cell damage. In addition, TRAF3IP3 knockdown can induce mitophagy, thus enhancing mitochondrial function. We further revealed that TRAF3IP3 can promote the degradation of NEDD4 protein. Moreover, TRAF3IP3 knockdown suppressed myocardial injury in I/R rats. TRAF3IP3 blocks mitophagy to exacerbate myocardial injury induced by I/R via mediating NEDD4 expression.

This study aimed to evaluate the correlation of plasma deoxycholic acid (DCA) levels with clinical and hemodynamic parameters in acute pulmonary embolism (APE) patients. Total 149 APE adult patients were prospectively recruited. Plasma DCA levels were measured using rapid resolution liquid chromatography-quadrupole time-of-flight mass spectrometry. Baseline clinical and hemodynamic parameters were evaluated according to plasma DCA levels. The plasma DCA levels were significantly lower in APE patients than in those without APE (P < 0.001). APE patients with adverse events had lower plasma DCA levels (P < 0.001). Low DCA group patients presented more adverse cardiac function, higher NT-proBNP levels (P = 0.010), and higher WHO functional class levels (P = 0.023). Low DCA group also presented with an adverse hemodynamic status, with higher pulmonary vascular resistance levels (P = 0.027) and lower cardiac index levels (P = 0.024). Both cardiac function and hemodynamic parameters correlated well with plasma DCA levels. Kaplan-Meier survival analysis demonstrated that APE patients with lower plasma DCA levels had a significantly higher event rate (P = 0.009). In the univariate and multivariate Cox regression analyses, the plasma DCA level was an independent predictor of clinical worsening events after adjusting for age, sex, WHO functional class, NT-proBNP level, pulmonary vascular resistance, and cardiac index (HR 0.370, 95% CI 0.161, 0.852; P = 0.019). Low plasma DCA levels predicted adverse cardiac function and hemodynamic collapse. A low DCA level was correlated with a higher clinical worsening event rate and could be an independent predictor of clinical outcomes in multivariate analysis.

Aluminum phosphide (AlP) is the main component of rice tablets (a pesticide), which produces phosphine gas (PH3) when exposed to stomach acid. The most important symptoms of PH3 toxicity include, lethargy, tachycardia, hypotension, and cardiac shock. It was shown that Iodine can chemically react with PH3, and the purpose of this study is to investigate the protective effects of Lugol solution in poisoning with rice tablets. Five doses (12, 15, 21, 23, and 25 mg/kg) of AlP were selected, for calculating its lethal dose (LD50). Then, the rats were divided into 4 groups: AlP, Lugol, AlP + Lugol, and Almond oil (as a control). After 4 h, the blood pressure and electrocardiogram (ECG) were recorded, and blood samples were obtained for biochemical tests, then liver, lung, kidney, heart, and brain tissues were removed for histopathological examination. The results of the blood pressure showed no significant changes (P > 0.05). In ECG, the PR interval showed a significant decrease in the AlP + Lugol group (P < 0.05). In biochemical tests, LDH, Ca²⁺, Creatinine, ALP, Mg²⁺, and K⁺ represented significant decreases in AlP + Lugol compared to the AlP group (P < 0.05). Also, the administration of Lugol's solution to AlP-poisoned rats resulted in a significant decrease in malondialdehyde levels and a significant increase in catalase activity (P < 0.05). Histopathological evaluation indicates that Lugol improves changes in the lungs, kidneys, brain, and heart. Our results showed that the Lugol solution could reduce tissue damage and oxidative stress in AlP-poisoned rats. We assume that the positive effects of Lugol on pulmonary and cardiac tissues are due to its ability to react directly with PH3.

Diabetic cardiomyopathy (DCM) is one of the serious complications of type 2 diabetes mellitus. Vasant Kusumakar Rasa (VKR) is a Herbo-metallic formulation reported in Ayurveda, an Indian system of medicine. The present work was designed to study the effect of VKR in cardiomyopathy in type 2 diabetic rats. Diabetes was induced by feeding a high-fat diet (HFD) for 2 weeks followed by streptozotocin (STZ) administration (35 mg/kg i.p.). VKR was administered orally at dose of 28 and 56 mg/kg once a day for 16 weeks. The results of the study indicated that VKR treatment significantly improved the glycemic and lipid profile, serum insulin, CK-MB, LDH, and cardiac troponin-I when compared to diabetic control animals. VKR treatment in rats significantly improved the hemodynamic parameters and cardiac tissue levels of TNF-α, IL-1β, and IL- 6 were also reduced. Antioxidant enzymes such as GSH, SOD, and catalase were improved in all treatment groups. Heart sections stained with H & E and Masson's trichome showed decreased damage to histoarchitecture of the myocardium. Expression of PI3K, Akt, and GLUT4 in the myocardium was upregulated after 16 weeks of VKR treatment. The study data suggested the cardioprotective capability of VKR in the management of diabetic cardiomyopathy in rats.

The population in the areas neighboring the Semipalatinsk Nuclear Test Site (SNTS) in the eastern region of Kazakhstan faces increased cardiovascular disease (CVD) risk. Previous research has not explored gene polymorphisms related to CVD in this population. Therefore, the present study examines the prevalence of six CVD-associated genotypes in three generations exposed to SNTS radiation. The genotyping of ApoE Leu28 → Pro, AGT Met174 → Thr, AGT Met235 → Thr, eNOS T786 → C, PON1 Gln192 → Arg, and EDN 1 Lys198 → Asn was performed using real-time polymerase chain reaction. The present study encompassed a cohort of 218 participants with a familial history of arterial hypertension and/or carotid artery disease spanning at least three generations. The analysis unveiled significant disparities in the prevalence of ApoE Leu28 → Pro, eNOS T786 → C, and PON1 Gln192 → Arg genotypes across different generations. Furthermore, a substantial variation in the distribution of the eNOS T786 → C genotype was observed between individuals of Kazakh and Russian ethnicities. Nevertheless, no significant discrepancies were detected in the frequencies of the investigated genotypes between genders. Further research in this area is warranted to enhance the understanding of the genetic factors contributing to CVD in the population exposed to radiation from the SNTS. Specifically, future studies should broaden the scope of genetic polymorphisms investigated and include representatives of healthy individuals who have not been exposed to radiation as controls.

Cardiovascular disease remains the leading cause of death worldwide, with acute myocardial infarction and anticancer drug-induced cardiotoxicity being the significant factors. The most effective treatment for acute myocardial infarction is rapid restoration of coronary blood flow by thrombolytic therapy or percutaneous coronary intervention. However, myocardial ischemia-reperfusion injury (MI/RI) after reperfusion therapy is common in acute myocardial infarction, thus affecting the prognosis of patients with acute myocardial infarction. There is no effective treatment for MI/RI. Anthracyclines such as Doxorubicin (DOX) have limited clinical use due to their cardiotoxicity, and the mechanism of DOX-induced cardiac injury is complex and not yet fully understood. N6-methyladenosine (m6A) plays a crucial role in many biological processes. Emerging evidence suggests that m6A methylation plays a critical regulatory role in MI/RI and DOX-induced cardiotoxicity (DIC), suggesting that m6A may serve as a novel biomarker and therapeutic target for MI/RI and DIC. M6A methylation may mediate the pathophysiological processes of MI/RI and DIC by regulating cellular autophagy, apoptosis, oxidative stress, and inflammatory response. In this paper, we first focus on the relationship between m6A methylation and MI/RI, then further elucidate that m6A methylation may mediate the pathophysiological process of MI/RI through the regulation of cellular autophagy, apoptosis, oxidative stress, and inflammatory response. Finally, briefly outline the roles played by m6A in DIC, which will provide a new methodology and direction for the research and treatment of MI/RI and DIC.