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Genetic Polymorphisms in Cardiovascular Disease: Effects Across Three Generations Exposed to Radiation from the Semipalatinsk Nuclear Test Site. 心血管疾病的基因多态性:暴露于塞米巴拉金斯克核试验场辐射的三代人的影响。
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-19 DOI: 10.1007/s12012-024-09885-y
Geir Bjørklund, Lyudmila Pivina, Yuliya Semenova

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.

哈萨克斯坦东部塞米巴拉金斯克核试验场(SNTS)附近地区的居民面临着更高的心血管疾病(CVD)风险。以往的研究尚未探究该人群中与心血管疾病相关的基因多态性。因此,本研究调查了暴露于 SNTS 辐射的三代人中六种心血管疾病相关基因型的流行情况。研究采用实时聚合酶链式反应法对 ApoE Leu28 → Pro、AGT Met174 → Thr、AGT Met235 → Thr、eNOS T786 → C、PON1 Gln192 → Arg 和 EDN 1 Lys198 → Asn 进行了基因分型。本研究涵盖了至少三代有动脉高血压和/或颈动脉疾病家族史的 218 名参与者。分析结果显示,不同世代的载脂蛋白E Leu28 → Pro、eNOS T786 → C和PON1 Gln192 → Arg基因型的患病率存在显著差异。此外,还观察到哈萨克族和俄罗斯族个体之间的 eNOS T786 → C 基因型分布存在很大差异。不过,在所调查的基因型频率中,没有发现性别间存在明显差异。有必要在这一领域开展进一步研究,以加深对暴露于 SNTS 辐射的人群中导致心血管疾病的遗传因素的了解。具体来说,未来的研究应扩大基因多态性的调查范围,并将未受辐射的健康人作为对照。
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引用次数: 0
Role of M6a Methylation in Myocardial Ischemia-Reperfusion Injury and Doxorubicin-Induced Cardiotoxicity. M6a 甲基化在心肌缺血再灌注损伤和多柔比星诱导的心脏毒性中的作用
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-18 DOI: 10.1007/s12012-024-09898-7
Yanfang Liu, Hui Wu, Gang Zhou, Dong Zhang, Qingzhuo Yang, Yi Li, Xiaoting Yang, Jianfeng Sun

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.

心血管疾病仍然是全球死亡的主要原因,其中急性心肌梗死和抗癌药物引起的心脏毒性是重要因素。急性心肌梗死最有效的治疗方法是通过溶栓疗法或经皮冠状动脉介入治疗迅速恢复冠状动脉血流。然而,再灌注治疗后的心肌缺血再灌注损伤(MI/RI)在急性心肌梗死中很常见,从而影响急性心肌梗死患者的预后。目前尚无有效治疗 MI/RI 的方法。多柔比星(DOX)等蒽环类药物因其心脏毒性而限制了临床应用,而 DOX 诱导心脏损伤的机制十分复杂,尚未完全明了。N6-甲基腺苷(m6A)在许多生物过程中发挥着至关重要的作用。新的证据表明,m6A 甲基化在 MI/RI 和 DOX 诱导的心脏毒性(DIC)中起着关键的调节作用,这表明 m6A 可作为 MI/RI 和 DIC 的新型生物标记物和治疗靶点。M6A 甲基化可能通过调节细胞自噬、细胞凋亡、氧化应激和炎症反应来介导 MI/RI 和 DIC 的病理生理过程。本文首先关注 m6A 甲基化与 MI/RI 的关系,然后进一步阐明 m6A 甲基化可能通过调控细胞自噬、凋亡、氧化应激和炎症反应介导 MI/RI 的病理生理过程。最后,简要概述了 m6A 在 DIC 中的作用,这将为 MI/RI 和 DIC 的研究和治疗提供新的方法和方向。
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引用次数: 0
Depleted Housing Elicits Cardiopulmonary Dysfunction After a Single Flaming Eucalyptus Wildfire Smoke Exposure in a Sex-Specific Manner in ApoE Knockout Mice. 在载脂蛋白E基因敲除小鼠暴露于一次燃烧的桉树野火烟雾后,贫化住房会以性别特异性方式引起心肺功能障碍。
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-24 DOI: 10.1007/s12012-024-09897-8
Michelle Fiamingo, Sydnie Toler, Kaleb Lee, Wendy Oshiro, Todd Krantz, Paul Evansky, David Davies, M Ian Gilmour, Aimen Farraj, Mehdi S Hazari

Although it is well established that wildfire smoke exposure can increase cardiovascular morbidity and mortality, the combined effects of non-chemical stressors and wildfire smoke remains understudied. Housing is a non-chemical stressor that is a major determinant of cardiovascular health, however, disparities in neighborhood and social status have exacerbated the cardiovascular health gaps within the United States. Further, pre-existing cardiovascular morbidities, such as atherosclerosis, can worsen the response to wildfire smoke exposures. This represents a potentially hazardous interaction between inadequate housing and stress, cardiovascular morbidities, and worsened responses to wildfire smoke exposures. The purpose of this study was to examine the effects of enriched (EH) versus depleted (DH) housing on pulmonary and cardiovascular responses to a single flaming eucalyptus wildfire smoke (WS) exposure in male and female apolipoprotein E (ApoE) knockout mice, which develop an atherosclerosis-like phenotype. The results of this study show that cardiopulmonary responses to WS exposure occur in a sex-specific manner. EH blunts adverse WS-induced ventilatory responses, specifically an increase in tidal volume (TV), expiratory time (Te), and relaxation time (RT) after a WS exposure, but only in females. EH also blunted an increase in isovolumic relaxation time (IVRT) and the myocardial performance index (MPI) 1-week after exposures, also only in females. Our results suggest that housing alters the cardiovascular response to a single WS exposure, and that DH might cause increased susceptibility to environmental exposures that manifest in altered ventilation patterns and diastolic dysfunction in a sex-specific manner.

尽管野火烟雾暴露会增加心血管疾病的发病率和死亡率已得到公认,但对非化学压力源和野火烟雾的综合影响的研究仍然不足。住房是一种非化学压力源,是心血管健康的主要决定因素,然而,邻里和社会地位的差异加剧了美国的心血管健康差距。此外,原有的心血管疾病(如动脉粥样硬化)会加重对野火烟雾的反应。这就意味着住房不足和压力、心血管疾病以及对野火烟雾暴露反应的恶化之间可能存在危险的相互作用。本研究的目的是检测富集(EH)和贫瘠(DH)饲养环境对雌雄载脂蛋白E(ApoE)基因敲除小鼠肺部和心血管对单次火焰桉树野火烟雾(WS)暴露的反应的影响。这项研究的结果表明,暴露于 WS 后的心肺反应具有性别特异性。EH 可减弱 WS 诱导的不良通气反应,特别是 WS 暴露后潮气量(TV)、呼气时间(Te)和松弛时间(RT)的增加,但仅限于雌性。在接触 WS 1 周后,EH 也会减弱等容舒张时间(IVRT)和心肌性能指数(MPI)的增加,同样只针对雌性动物。我们的研究结果表明,居住环境会改变心血管对单次WS暴露的反应,DH可能会导致对环境暴露的易感性增加,并以性别特异性的方式表现为通气模式改变和舒张功能障碍。
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引用次数: 0
Ciprofloxacin Accelerates Angiotensin-II-Induced Vascular Smooth Muscle Cells Senescence Through Modulating AMPK/ROS pathway in Aortic Aneurysm and Dissection. 环丙沙星通过调节主动脉瘤和主动脉夹层中的 AMPK/ROS 通路加速血管紧张素-II 诱导的血管平滑肌细胞衰老
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-08-13 DOI: 10.1007/s12012-024-09892-z
Weiyue Zeng, Yaowen Liang, Shangjun Huang, Jiarui Zhang, Cong Mai, Binbin He, Linli Shi, Baojuan Liu, Weifeng Li, Xiaoran Huang, Xin Li
<p><p>Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-β-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-β-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-β-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate tha
主动脉瘤和夹层(AAD)是一种严重威胁生命的心血管疾病,发病率和死亡率都很高。临床和动物研究无可辩驳地表明,氟喹诺酮类药物(一种治疗感染的常用抗生素)会显著增加主动脉瘤和夹层的发病风险。尽管如此,氟喹诺酮类药物导致 AAD 的确切机制仍不清楚。因此,本研究旨在明确研究环丙沙星(氟喹诺酮类抗生素的一种)在 AAD 进展过程中的分子机制和作用。研究人员从 GEO 数据集中收集了主动脉转录组数据,以检测健康供体和 AAD 患者之间表达不同的基因和通路。从主动脉中分离出人类原代血管平滑肌细胞(VSMC)。在暴露于 110ug/ml 环丙沙星或 100 nmol/L AngII(任选其一或二者结合)72 小时后,通过 SA-β-gal 染色鉴定衰老细胞。MitoTracker 染色用于检测各组线粒体的形态。使用 MitoSox 和 DCFH-DA 染色法测量细胞活性氧(ROS)水平。用 Western 印迹法检测蛋白质表达水平。我们对健康供体和 AAD 患者的转录组数据进行了分析,发现后者的细胞衰老相关信号通路发生了显著变化。然后,我们分别从健康供体(对照组-VSMCs)和患者(AAD-VSMCs)的主动脉组织中分离并鉴定了人类原发性 VSMCs。我们发现,与对照组-VSMCs 相比,患者的 VSMCs 表现出衰老表型。更高水平的 p21 和 p16 以及升高的 SA-β-gal 活性都证明了这一点。我们还发现,环丙沙星的预处理促进了血管紧张素 II 诱导的对照-VSMC 细胞衰老。这表现在 SA-β-gal 活性增加、细胞增殖减少以及 p21 和 p16 蛋白水平升高。此外,我们还发现血管紧张素 II(AngII)通过促进 ROS 生成诱导 VSMC 衰老。我们使用 DCFH-DA 和 mitoSOX 染色法发现,环丙沙星和 AngII 预处理组的 ROS 水平比车辆组或单独使用组进一步升高。此外,JC-1 染色显示,环丙沙星和 AngII 组合组的线粒体膜电位较其他组明显下降。与其他三组相比,环丙沙星加 AngII 预处理组能进一步诱导线粒体分裂,mitoTracker 染色和 Western 印迹检测均证明了这一点。从机理上讲,我们发现环丙沙星通过抑制 AMPK 信号的磷酸化,破坏了 VSMC 线粒体裂变和融合的动态平衡。这导致线粒体功能障碍和 ROS 生成,从而加剧了 AngII 诱导的细胞衰老。然而,用 AMPK 激活剂处理可部分缓解这些影响。我们的数据表明,环丙沙星可能通过调节 AMPK/ROS 信号加速 AngII 诱导的血管内皮细胞衰老,进而加速 AAD 的进展。
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引用次数: 0
Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia. 金属阳离子与肝素诱导的血小板减少症中抗-PF4/肝素抗体反应的关系
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-17 DOI: 10.1007/s12012-024-09895-w
Jason B Giles, Kiana L Martinez, Heidi E Steiner, Andrew Klein, Aikseng Ooi, Julie Pryor, Nancy Sweitzer, Deborah Fuchs, Jason H Karnes

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD405] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD405 ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts.

肝素诱导的血小板减少症(HIT)是一种针对肝素和血小板因子 4(PF4)复合物的抗体介导的免疫反应。肝素和 PF4 之间的静电相互作用对于 HIT 中出现的抗 PF4/肝素抗体反应至关重要。金属阳离子与肝素的结合会引起构象变化和肝素分子的电荷中和,阳离子与肝素的结合可调节肝素结合伙伴的特异性和亲和力。然而,金属阳离子与肝素结合对抗 PF4/肝素抗体反应的影响尚未确定。在此,我们利用电感耦合等离子体质谱法(ICP-MS)对患者血浆中的 16 种金属阳离子进行了定量分析,并检测了一组肝素治疗患者临床怀疑 HIT 后抗 PF4/肝素 IgG 水平和血小板计数的相关性。该组患者(n = 32)的平均年龄为 60.53(SD = 14.31)岁,平均抗-PF4/肝素抗体光密度 [OD405] 为 0.93(SD = 1.21)个单位,主要为女性(n = 23)。与抗体阴性患者相比,抗-PF4/肝素抗体检测结果呈阳性(OD405 ≥ 0.5 单位)的患者更年轻,体重和体重指数(BMI)更高,血清素释放测定(SRA)结果呈阳性的可能性更大。我们观察到抗体阳性组和抗体阴性组在钠和铝方面存在统计学差异,抗 PF4/肝素抗体水平与钠和银存在显著相关性。虽然钠浓度的差异与抗体阳性状态有关,并与抗体水平相关,但没有进行复制。为了证实我们观察到的关联性,有必要进行更多的研究,包括体外结合研究和更大规模的观察性队列研究。
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引用次数: 0
Characterization of Mild Delayed Gestational Hypertension in Rats Following Ozone Exposure. 臭氧暴露后大鼠轻度延迟性妊娠高血压的特征。
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-04 DOI: 10.1007/s12012-024-09887-w
Russell Hunter, Thomas Wilson, Selita Lucas, David Scieszka, Barry Bleske, Andrew Ottens, Ryan Ashley, Carolyn Pace, Nancy Kanagy, Matthew Campen

The contribution of air pollution-induced cardiopulmonary damage on the development of hypertensive disorders of pregnancy and other adverse outcomes of pregnancy has gained increased attention as epidemiological data continue to highlight spatiotemporal pregnancy trends related to air pollution exposure. However clinical mechanistic data surrounding gestational complications remain sparse, necessitating the need for the use of animal models to study these types of complications of pregnancy. The current study seeks to examine the real-time effects of mid-gestational ozone exposure on maternal blood pressure and body temperature through the use of radiotelemetry in a rat model. The exposure resulted in acute depression of heart rate and core body temperature as compared to control animals. Ozone-exposed animals also presented with a slight but significant increase in arterial blood pressure which was perpetuated until term. The data presented here illustrates the feasibility of murine models to assess cardiovascular complications caused by inhaled toxicants during the window of pregnancy.

随着流行病学数据不断突显出与空气污染暴露相关的妊娠时空趋势,空气污染诱发的心肺损伤对妊娠高血压疾病和其他不良妊娠结局的发生所起的作用日益受到关注。然而,有关妊娠并发症的临床机理数据仍然很少,因此有必要使用动物模型来研究这类妊娠并发症。目前的研究试图通过在大鼠模型中使用放射性遥测技术,研究妊娠中期臭氧暴露对母体血压和体温的实时影响。与对照组动物相比,接触臭氧会导致心率和核心体温急性下降。接触臭氧的动物动脉血压也会出现轻微但显著的升高,这种情况一直持续到分娩。本文提供的数据表明,用小鼠模型来评估妊娠期吸入有毒物质引起的心血管并发症是可行的。
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引用次数: 0
Cardiotoxicity of Cadmium and Its Effects on Heart Efficiency During Early and Late Chick Embryogenesis. 镉的心脏毒性及其对雏鸡早期和晚期胚胎发育过程中心脏效率的影响
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-24 DOI: 10.1007/s12012-024-09894-x
Reda A Ali, Eatemad A Awadalla, Amal S Hamed, Dalia Elzahraa F Mostafa

Cadmium (Cd) is a dangerous heavy metal that is non-degradable in the environment. Many organs can accumulate Cd and adversely affect organ function and health. Cd is considered as a teratogenic and embryotoxic agent. This study aims to evaluate the teratogenicity of Cd at concentrations lesser than the permissible and its effects on the heart during chick embryogenesis. Fertilized eggs of the chick Gallus domesticus were divided into; control, saline injected and four experimental groups injected with single doses of 5, 25, 50 or 75 µM of CdCl2. Histological observations of the heart before hatching and the cardiomyocytes after hatching were recorded. Morphometric measurements of heart chambers were achieved at 3, 4 and 6 days of incubation. Electrocardiograph and respiratory rate were recorded at tenth day. Different cardiac problems had been brought on by Cd. In comparison to controls, the heart looked much larger, and in certain cases, growth retardation was seen. Degeneration in heart walls and malformations of dorsal aorta were noticed. Morphometrically, the width and wall thickness of heart chambers showed significant changes. Heart beats and respiratory rate significantly decreased compared to control. The cardiotoxic effect of Cd on heart compartments structure and function was dose dependent. One of Cd toxicity is its ability to induce cellular oxidative stress. The heart in particular is sensitive to oxidative stress. Cardiac oxidative stress might intensify heart failure and promote disease progression. Calcium is one of the components that is needed for normal heart work. Cd might interfere with calcium metabolism by removing it from the body.

镉(Cd)是一种危险的重金属,在环境中不可降解。许多器官都会积聚镉,对器官功能和健康产生不利影响。镉被认为具有致畸和胚胎毒性。本研究旨在评估镉在低于允许浓度时的致畸性及其对小鸡胚胎发育过程中心脏的影响。受精卵分为对照组、注射生理盐水组和注射单剂量 5、25、50 或 75 µM 氯化镉的四个实验组。对孵化前的心脏和孵化后的心肌细胞进行组织学观察。在孵化 3、4 和 6 天时对心腔进行形态测量。第十天记录心电图和呼吸频率。镉引起了不同的心脏问题。与对照组相比,小鼠的心脏看起来要大得多,在某些情况下还会出现生长迟缓。还发现心壁退化和背主动脉畸形。从形态学角度看,心室的宽度和壁厚发生了显著变化。与对照组相比,心跳和呼吸频率明显下降。镉对心脏结构和功能的毒性作用与剂量有关。镉的毒性之一是其诱导细胞氧化应激的能力。心脏对氧化应激尤其敏感。心脏氧化应激可能会加剧心力衰竭并促进疾病进展。钙是心脏正常工作所需的成分之一。镉可能会将钙排出体外,从而干扰钙的代谢。
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引用次数: 0
Activation AMPK in Hypothalamic Paraventricular Nucleus Improves Renovascular Hypertension Through ERK1/2-NF-κB Pathway. 通过ERK1/2-NF-κB途径激活下丘脑室旁核中的AMPK改善肾血管性高血压
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-15 DOI: 10.1007/s12012-024-09888-9
Li-Yan Fu, Yu Yang, Rui-Juan Li, Abdoulaye Issotina Zibrila, Hua Tian, Xiu-Yue Jia, Jin-An Qiao, Jin-Min Wu, Jie Qi, Xiao-Jing Yu, Yu-Ming Kang

Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 μg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.

高血压是一种全球流行的疾病,但其发病机理在很大程度上仍不清楚。AMP激活蛋白激酶(AMPK)是细胞能量代谢的营养敏感信号,对高血压的发病有一定影响。此前,我们发现在高血压大鼠的下丘脑室旁核(PVN)中,AMPK 的磷酸化(p-)形式下调,血管紧张素 II 1 型受体(AT1-R)和 p-ERK1/2 上调。然而,高血压期间下丘脑室旁核 AMPK 与 AT1-R 之间关系的确切机制仍不清楚。因此,我们假设 AMPK 通过 ERK1/2-NF-κB 通路调节 PVN 中的 AT1-R,从而抑制交感神经活动并改善高血压。为了验证这一假设,我们采用了通过双肾单夹(2K1C)和假手术(SHAM)建立的新血管性高血压动物模型。将人工脑脊液(aCSF)(用作载体)或 5-氨基-1-β-D-呋喃核糖基咪唑-4-甲酰胺(AICAR,一种 AMPK 激活剂,60 μg/天)微量注射到这些大鼠的 PVN 中,持续 4 周。在 2K1C 大鼠中,收缩压(SBP)和循环去甲肾上腺素(NE)均有所增加。此外,与 SHAM 大鼠相比,高血压大鼠 PVN 中 p-AMPK 和 p-AMPK/AMPK 表达降低,p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 表达升高,NF-κB p65 活性增加。给 2K1C 大鼠双侧 PVN 注射 AMPK 激活剂 AICAR 四周后,NE 水平和 SBP 均有所降低,p-AMPK 和 p-AMPK/AMPK 的表达增加,NF-κB p65 活性降低,p-ERK1/2、p-ERK1/2/ERK1/2 和 AT1-R 的表达减少。这项研究的数据表明,激活 PVN 中的 AMPK 可通过抑制 ERK1/2-NF-κB 通路抑制 AT1-R 的表达,降低交感神经系统的活性,从而改善高血压。
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引用次数: 0
Mitotherapy with Fresh Isolated Cardiac Mitochondria Via Injection Into Blood Reduces Aluminum Phosphide-Induced Mortality and Protects Cardiac Tissue Against Oxidative Stress and Mitochondrial Damages. 通过向血液中注射新鲜分离的心脏线粒体进行光疗,可降低磷化铝诱导的死亡率,并保护心脏组织免受氧化应激和线粒体损伤。
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1007/s12012-024-09896-9
Mohammad Shabani, Saleh Khezri, Ahmad Salimi

The hallmark of aluminum phosphide (AlP) poisoning is heart failure in victims which is associated with reactive oxygen species (ROS), mitochondrial dysfunction, oxidative stress, alteration in antioxidant defense system and depletion of ATP in cardiomyocytes. In the present study, we hypothesized that the injection of isolated mitochondria into blood or mitochondrial transplantation can likely create a primary target for phosphine released from AlP and inhibit AlP-induced mortality and cardiotoxicity in rat. Male, Wistar, healthy and adult rats were randomly divided into 5 groups as control, AlP (12.5 mg/kg, orally), AlP + mitochondria (125 µg/kg), AlP + mitochondria (250 µg/kg) and mitochondria (250 µg/kg) alone. Functional and intact mitochondria isolated from rat heart and transplantation was carried out via tail vein, 30 min after exposure to AlP. Survival rate, histopathological alterations, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters were monitored and analyzed during 30 days. We found that injection of healthy mitochondria into blood at concentrations of 125 and 250 125 µg/ml significantly increased the survival of rats up to 40% and 56.25% respectively, during 30 days. Moreover, we observed that mitochondria injection into blood decreased histopathological damages, cardiac biochemical markers, oxidative stress and mitochondrial toxicity parameters. To our knowledge, the current study is the first report in the literature that demonstrated good therapeutic effects of mitochondrial transplantation in AlP-induced mortality and cardiotoxicity. The findings of the present study suggests that injection of exogenous mitochondria into blood could be an effective therapeutic strategy in treating AlP poisoning.

磷化铝(AlP)中毒的特征是受害者心力衰竭,这与活性氧(ROS)、线粒体功能障碍、氧化应激、抗氧化防御系统的改变以及心肌细胞中 ATP 的耗竭有关。在本研究中,我们假设向血液中注入分离的线粒体或线粒体移植可能会成为 AlP 释放的磷化氢的主要靶点,并抑制 AlP 引起的大鼠死亡和心脏毒性。健康成年雄性 Wistar 大鼠被随机分为 5 组,分别为对照组、AlP 组(12.5 毫克/千克,口服)、AlP + 线粒体组(125 微克/千克)、AlP + 线粒体组(250 微克/千克)和单独线粒体组(250 微克/千克)。从大鼠心脏中分离出功能完整的线粒体,并在接触 AlP 30 分钟后通过尾静脉进行移植。在 30 天内对存活率、组织病理学改变、心脏生化指标、氧化应激和线粒体毒性参数进行了监测和分析。我们发现,向血液中注射浓度为 125 和 250 125 µg/ml 的健康线粒体可显著提高大鼠的存活率,30 天内存活率分别达到 40% 和 56.25%。此外,我们还观察到,向血液中注入线粒体可减少组织病理学损伤、心脏生化指标、氧化应激和线粒体毒性参数。据我们所知,本研究是文献中首次报道线粒体移植对 AlP 引起的死亡和心脏毒性有良好的治疗效果。本研究结果表明,向血液中注入外源性线粒体可能是治疗 AlP 中毒的一种有效治疗策略。
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引用次数: 0
Levamisole Impairs Vascular Function by Blocking α-Adrenergic Receptors and Reducing NO Bioavailability in Rabbit Renal Artery. 左旋咪唑通过阻断α-肾上腺素能受体和降低氮氧化物在兔肾动脉中的生物利用率损害血管功能
IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1007/s12012-024-09879-w
Sol Guerra-Ojeda, Patricia Marchio, Andrea Suarez, Martin Aldasoro, Soraya L Valles, Patricia Genoves, Jose M Vila, Maria D Mauricio

Levamisole is an anthelmintic drug restricted to veterinary use but is currently detected as the most widely used cocaine cutting agent in European countries. Levamisole-adulterated cocaine has been linked to acute kidney injury, marked by a decrease in glomerular filtration rate, which involves reduced renal blood flow, but data on the alteration of renovascular response produced by levamisole are scarce. Renal arteries were isolated from healthy rabbits and used for isometric tension recording in organ baths and protein analysis. We provide evidence that depending on its concentration, levamisole modulates renovascular tone by acting as a non-selective α-adrenergic receptor blocker and down-regulates α1-adrenoceptor expression. Furthermore, levamisole impairs the endothelium-dependent relaxation induced by acetylcholine without modifying endothelial nitric oxide synthase (eNOS) expression. However, exposure to superoxide dismutase (SOD) partially prevents the impairment of ACh-induced relaxation by levamisole. This response is consistent with a down-regulation of SOD1 and an up-regulation of NADPH oxidase 4 (Nox4), suggesting that endothelial NO loss is due to increased local oxidative stress. Our findings demonstrate that levamisole can interfere with renal blood flow and the coordinated response to a vasodilator stimulus, which could worsen the deleterious consequences of cocaine use.

左旋咪唑是一种仅限于兽医使用的抗蠕虫药物,但目前在欧洲国家被检测出是使用最广泛的可卡因切割剂。掺杂左旋咪唑的可卡因与急性肾损伤有关,其特征是肾小球滤过率下降,这涉及肾血流量减少,但有关左旋咪唑改变肾血管反应的数据很少。我们从健康兔子身上分离出肾动脉,在器官浴中记录等长张力并进行蛋白质分析。我们提供的证据表明,左旋咪唑可作为一种非选择性α肾上腺素能受体阻断剂,并下调α1肾上腺素受体的表达,从而调节肾动脉张力,具体取决于其浓度。此外,左旋咪唑会损害乙酰胆碱诱导的内皮依赖性松弛,但不会改变内皮一氧化氮合酶(eNOS)的表达。然而,暴露于超氧化物歧化酶(SOD)可部分防止左旋咪唑对乙酰胆碱诱导的内皮松弛的损害。这种反应与 SOD1 的下调和 NADPH 氧化酶 4(Nox4)的上调相一致,表明内皮 NO 的损失是由于局部氧化应激增加所致。我们的研究结果表明,左旋咪唑可干扰肾血流和对血管扩张刺激的协调反应,这可能会加重使用可卡因的有害后果。
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引用次数: 0
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Cardiovascular Toxicology
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