Journal of molecular and cellular cardiology最新文献_第5页

Beneficial effects of aryl hydrocarbon receptor activation on post-infarction myocardial metabolism, inflammation and fibrosis: implications from multi-omics 芳烃受体激活对梗死后心肌代谢、炎症和纤维化的有益影响：来自多组学的意义。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-21 DOI: 10.1016/j.yjmcc.2025.10.006

Yong Chu , Jiang Zhu , Shuaijie Chen , Xiaoyan Lin , Zhongxing Zhou , Ruming Shen , Hongzhuang Wang , Longqing Chen , Jinxiu Lin , Hailin Zhang , Dajun Chai

Background

Post-infarction metabolism changes, inflammatory responses, and fibrosis are crucial contributors to adverse cardiac remodeling. 2-(1′H-indole-3′‑carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), the aryl hydrocarbon receptor (AHR) ligand, has demonstrated effective AHR activation, yet its impact and mechanisms in myocardial infarction (MI) remain unclear.

Methods

The MI model was established by ligating left anterior coronary artery, and ITE was administered for 4 weeks. Echocardiography and hemodynamic monitoring were used to assess cardiac structure and function. Hematoxylin-eosin and Masson's trichrome were used to examine morphology and collagen deposition. Transmission electron microscopy was employed to examine mitochondrial morphology. The transcriptome and metabolome were used to screen for key targets and pathways. Hypoxic neonatal rat cardiomyocytes and fibroblasts models combined with adenoviral AHR knockdown were used to verify key targets and pathways.

Results

ITE intervention significantly improved cardiac structure and function, mitochondrial morphology, fibrosis and inflammation in MI rats. Multi-omics revealed that differentially expressed genes and metabolites were enriched in glucose metabolism related pathways and identified a key target, HK2. Compared to MI group, ITE significantly improved the expression of key enzymes in glucose metabolism after MI. In vitro, AHR activation by ITE and tapinarof significantly ameliorated hypoxia-induced abnormalities in HK2, CISY, OGDH, fibrosis, and inflammatory markers, while hexokinase inhibitor eliminated the beneficial effects of ITE. Moreover, AHR knockdown impairs glucose metabolism and promotes inflammation and fibrosis.

Conclusion

The AHR activation by ITE mitigates inflammation and fibrosis, improves cardiac structure and function by promoting HK2 and glucose metabolism after MI.

背景：梗死后代谢改变、炎症反应和纤维化是不良心脏重构的关键因素。2-（1‘ h -吲哚-3’羰基）-噻唑-4-羧酸甲酯（ITE）是芳烃受体（AHR）的配体，已被证明能有效激活AHR，但其在心肌梗死（MI）中的作用和机制尚不清楚。方法：结扎左冠状动脉前支，建立心肌梗死模型，给药4 周。超声心动图和血流动力学监测评估心脏结构和功能。苏木精-伊红和马松三色法检测形态学和胶原沉积。透射电镜观察线粒体形态。转录组和代谢组用于筛选关键靶点和途径。使用缺氧新生大鼠心肌细胞和成纤维细胞模型联合腺病毒AHR敲低来验证关键靶点和途径。结果：ITE干预显著改善心肌梗死大鼠心脏结构和功能、线粒体形态、纤维化和炎症。多组学显示，差异表达的基因和代谢物在糖代谢相关途径中富集，并确定了一个关键靶点HK2。与心肌梗死组相比，ITE可显著改善心肌梗死后糖代谢关键酶的表达。体外实验中，ITE和tapinarof激活AHR可显著改善缺氧诱导的HK2、CISY、OGDH、纤维化和炎症标志物异常，而己糖激酶抑制剂可消除ITE的有益作用。此外，AHR敲低会损害葡萄糖代谢，促进炎症和纤维化。结论：ITE激活AHR可减轻心肌梗死后的炎症和纤维化，通过促进HK2和糖代谢改善心肌结构和功能。

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引用次数: 0

Modelling diabetes-associated metabolic stress in human multicellular cardiac microtissues 模拟人类多细胞心脏微组织中糖尿病相关的代谢应激。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-14 DOI: 10.1016/j.yjmcc.2025.10.004

Ren Jie Phang , Nan Su , Anne M. Kong , Shiang Y. Lim , Jarmon G. Lees

Type 2 diabetes is a global health crisis, closely associated with an increased risk of heart failure due to the development of diabetic cardiomyopathy. Progress in understanding the underlying mechanisms and identifying effective treatments has been limited by the lack of robust preclinical models that accurately mimic human cardiac physiology. Human induced pluripotent stem cells (iPSCs) offer the unique ability to generate large quantities of both cardiomyocytes and non-myocytes, enabling the development of advanced models for cardiovascular research. In this study, we present engineered 3D multicellular cardiac microtissues, comprising human iPSC-derived cardiomyocytes, endothelial cells, autonomic neurons, and cardiac fibroblasts, designed to provide a more physiologically relevant platform for investigating the effects of diabetogenic conditions on human heart tissue. Under diabetogenic conditions, these multicellular cardiac microtissues exhibited reduced viability, fibrotic marker expression, and prolonged systolic and diastolic phases, closely mirroring the contractile dysfunction observed in late-stage diabetic cardiomyopathy, outcomes not replicated in traditional 2D culture of cardiomyocytes or cardiomyocyte-only microtissues. Metformin treatment prevented the manifestation of diastolic dysfunction induced by diabetogenic conditions, demonstrating the utility of multicellular cardiac microtissues for drug assessment. Our findings emphasize the critical role of non-myocytes in the progression of cardiac dysfunction induced by hyperglycaemia and hyperlipidaemia, underscoring their importance in disease modelling. These iPSC-derived multicellular cardiac microtissues represent a significant advancement in preclinical models for diabetic cardiomyopathy, providing a more accurate platform for mechanistic studies and drug discovery.

2型糖尿病是一种全球性的健康危机，与糖尿病性心肌病引起的心力衰竭风险增加密切相关。由于缺乏准确模拟人类心脏生理学的强大临床前模型，在理解潜在机制和确定有效治疗方面的进展受到限制。人类诱导多能干细胞（iPSCs）提供了产生大量心肌细胞和非心肌细胞的独特能力，使心血管研究的先进模型得以发展。在这项研究中，我们提出了工程化的3D多细胞心脏微组织，包括人类ipsc衍生的心肌细胞、内皮细胞、自主神经元和心脏成纤维细胞，旨在为研究糖尿病对人类心脏组织的影响提供一个生理学上更相关的平台。在糖尿病发病条件下，这些多细胞心脏微组织表现出活力降低、纤维化标志物表达、收缩期和舒张期延长，与晚期糖尿病心肌病中观察到的收缩功能障碍密切相关，这些结果在传统的二维心肌细胞培养或仅心肌细胞的微组织中无法复制。二甲双胍治疗可防止糖尿病引起的舒张功能障碍，证明了多细胞心脏微组织在药物评估中的实用性。我们的研究结果强调了非肌细胞在高血糖和高脂血症引起的心功能障碍进展中的关键作用，强调了它们在疾病建模中的重要性。这些ipsc衍生的多细胞心脏微组织代表了糖尿病心肌病临床前模型的重大进展，为机制研究和药物发现提供了更准确的平台。

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引用次数: 0

Catecholaminergic stress results in signs of heart failure in PP2A-PR72 overexpressor mice 儿茶酚胺能应激导致PP2A-PR72过表达小鼠心力衰竭的迹象。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-12 DOI: 10.1016/j.yjmcc.2025.10.003

Paul Pauls , Larissa Fabritz , Julius R. Herting , Amanda Johann , Jule H. König , Jan S. Schulte , Matthias D. Seidl , Carolina E. Soppa , Uwe Kirchhefer

Background

It is unclear whether the increase in protein expression of PP2A regulatory subunit PR72 seen in human heart failure represents a primary compensatory mechanism or the final reaction to contractile decompensation. To address this question, we have explored the effects of chronic catecholaminergic stress in a transgenic (TG) mouse model with heart-specific overexpression of PR72 that exhibits hypercontractility at basal conditions.

Methods

Mice were treated with isoprenaline (ISO) or NaCl for 7 days using osmotic minipumps. Hearts or isolated cardiomyocytes from the animals were functionally examined.

Results

We could show (i) that PR72 expression is not only increased after chronic ISO stimulation but also in other different stress and insufficiency models. In TG mice, 7 days of ISO treatment led to (ii) increased hypertrophy, pulmonary edema, more fibrosis, and higher ACTA1 gene expression compared to wild-type (WT) mice. These effects were accompanied by (iii) a decrease in myocellular contractility and prolonged relaxation. Ca²⁺ transients (iv) showed correspondingly delayed decay kinetics in TG versus WT, while (v) the reduction of L-type calcium peak current by ISO treatment was less pronounced in TG cells. The decrease in RyR2 phosphorylation in TG (vi) supports a deterioration in contractility due to chronic ISO treatment in TG.

Conclusion

Our results indicate that the upregulation of PP2A-PR72 in various stress and heart failure models has a long-term effect, perpetuating the molecular and functional detrimental cardiac changes, if it does not have a triggering effect.

背景：目前尚不清楚人类心力衰竭中PP2A调节亚基PR72蛋白表达的增加是主要代偿机制还是对收缩代偿的最终反应。为了解决这个问题，我们探索了慢性儿茶酚胺能应激对转基因（TG）小鼠模型的影响，该模型具有心脏特异性PR72过表达，在基础条件下表现出过度收缩。方法：小鼠用渗透微型泵分别给予异丙肾上腺素（ISO）或NaCl治疗7 d。对动物的心脏或分离的心肌细胞进行功能检查。结果：我们可以发现(i)在慢性ISO刺激后，PR72的表达不仅增加，而且在其他不同的应激和不足模型中也增加。在TG小鼠中，与野生型（WT）小鼠相比，7 天的ISO治疗导致（ii）肥大，肺水肿，更多纤维化和更高的ACTA1基因表达。这些影响伴随着（iii）心肌细胞收缩力下降和松弛时间延长。与WT相比，Ca2+瞬态（iv）在TG中显示出相应的延迟衰变动力学，而(v) ISO处理对l型钙峰电流的降低在TG细胞中不太明显。TG中RyR2磷酸化的降低（vi）支持TG慢性ISO治疗导致的收缩性恶化。结论：我们的研究结果表明，在各种应激和心力衰竭模型中，PP2A-PR72的上调具有长期影响，即使没有触发效应，也会使分子和功能上的有害心脏变化永久化。

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引用次数: 0

Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial ischemia/reperfusion injury Nynrin通过抑制心肌缺血/再灌注损伤时线粒体通透性过渡孔打开来增强心功能。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-10 DOI: 10.1016/j.yjmcc.2025.10.002

Yuhan Wang , Yujing Li , Yanan Zhou , Hao Zhang , Jingyi Zang , Chaofan Yang , Zeyu Gao , Yu Hou , Moshi Song

Acute myocardial infarction (AMI) is a leading cause of cardiovascular disease-related death. Reperfusion therapies, although essential, can exacerbate damage through myocardial ischemia/reperfusion (I/R) injury. Cyclophilin D (CypD) and mitochondrial permeability transition pore (mPTP) opening have been identified as potential therapeutic targets for I/R injury. However, clinical trials with cyclosporin A (CsA) have shown mixed results, highlighting the urgent need for alternative strategies to suppress CypD expression or activity. In this study, we explored the role of Nynrin, a newly identified transcriptional repressor of peptidylprolyl isomerase F (Ppif) that encodes CypD, in mitigating I/R injury by regulating mPTP opening. We first observed that Nynrin was downregulated in adult mouse hearts subjected to I/R and in primary adult mouse cardiomyocytes upon oxygen-glucose deprivation/reperfusion (OGD/R). Subsequently, we generated a tamoxifen-inducible cardiomyocyte-specific Nynrin-knockout (Nynrin-cKO) mouse model, which was well-tolerated in otherwise normal adult mouse hearts. Notably, Nynrin-cKO mice exhibited exacerbated contractile dysfunction and cardiac injury, characterized by enhanced Ppif transcription, CypD expression, mPTP opening, and cardiomyocyte death when subjected to I/R. Furthermore, the exacerbated I/R-induced cardiac dysfunction in Nynrin-cKO mice was significantly reversed by CsA, an mPTP inhibitor that targets CypD, indicating that the intensified pathological manifestations in Nynrin-cKO mice during I/R injury were dependent on CypD and mPTP. Conversely, Nynrin overexpression in primary adult mouse cardiomyocytes blunted Ppif/CypD upregulation and restrained mPTP opening, thus reducing cardiomyocyte damage upon OGD/R. Taken together, our findings highlight the critical role of Nynrin in regulating CypD and mPTP in I/R injury and suggest that targeting Nynrin may be a promising therapeutic strategy for mitigating cardiac dysfunction in managing I/R injury.

急性心肌梗死（AMI）是心血管疾病相关死亡的主要原因。再灌注治疗虽然必不可少，但可通过心肌缺血/再灌注（I/R）损伤加重损伤。亲环蛋白D （CypD）和线粒体通透性过渡孔（mPTP）开放已被确定为I/R损伤的潜在治疗靶点。然而，环孢素A （CsA）的临床试验显示出不同的结果，强调迫切需要替代策略来抑制CypD的表达或活性。在这项研究中，我们探索了Nynrin的作用，Nynrin是一种新发现的编码CypD的肽基脯氨酸异构酶F （Ppif）的转录抑制因子，通过调节mPTP的开放来减轻I/R损伤。我们首先观察到，在I/R的成年小鼠心脏和氧-葡萄糖剥夺/再灌注（OGD/R）的成年小鼠心肌细胞中，Nynrin被下调。随后，我们建立了他莫昔芬诱导的心肌细胞特异性nynrin敲除（Nynrin-cKO）小鼠模型，该模型在正常成年小鼠心脏中耐受性良好。值得注意的是，Nynrin-cKO小鼠在I/R时表现出更严重的收缩功能障碍和心脏损伤，其特征是Ppif转录、CypD表达、mPTP开放和心肌细胞死亡增加。此外，针对CypD的mPTP抑制剂CsA可显著逆转I/R诱导的Nynrin-cKO小鼠心功能障碍加重，说明I/R损伤期间Nynrin-cKO小鼠的病理表现加重依赖于CypD和mPTP。相反，在原代成年小鼠心肌细胞中，Nynrin过表达会减弱Ppif/CypD的上调，抑制mPTP的开放，从而减轻OGD/R对心肌细胞的损伤。综上所述，我们的研究结果强调了Nynrin在I/R损伤中调节CypD和mPTP的关键作用，并表明靶向Nynrin可能是缓解I/R损伤心功能障碍的一种有希望的治疗策略。

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引用次数: 0

Multi-level expression profiling of cardiac and musculoskeletal Schwann cells in young and old mice 年轻和年老小鼠心脏和肌肉骨骼雪旺细胞的多层次表达谱。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-03 DOI: 10.1016/j.yjmcc.2025.10.001

Severin Haider , Dragana Stefanovska , Eliza Sassu , Claudia Domisch , Madelon Hossfeld , Pia Iaconianni , Stefanie Perez-Feliz , Franziska Schneider-Warme , Peter Kohl , Sebastian Preissl , Luis Hortells

Schwann cells (SC) are crucial for physiological impulse conduction in peripheral nerves. They produce myelin, provide axonal metabolic support, and contribute to reparatory processes after nerve injury. During aging, peripheral nerves acquire myelin structural anomalies and are characterized by a lower fraction of SC and a higher fraction of senescent cells. All these changes correlate with impaired electrical conduction and consequently altered function of target tissues including skeletal muscle weakness and cardiac arrhythmia. To characterize and compare cardiac and sciatic nerve SC, as well as to explore age-related differences in SC abundance and their properties, we analyzed two TdTomato reporter mouse strains to isolate Sox10 or Plp1 expressing SC. We performed RNA-sequencing on sorted TdTomato-positive cells from the heart and sciatic nerve and validated transcriptomic findings at the protein level using immunofluorescence. Our data reveal a pro-angiogenic profile in cardiac SC when compared to sciatic SC. In addition, higher levels of neural-death associated genes and lower gene and protein expression levels of the fatty acid co-transporter Fabp4/FABP4 are detected in cardiac SC from old compared to young mice, suggesting an aging-related impairment of fatty acid transport. Finally, sciatic SC activate collagen remodeling and increased pro-inflammatory signaling including TNFα. Thus, cardiac and musculoskeletal SC have different expression profiles, and undergo different changes during aging, which may contribute to impaired nerve function in both organ systems.

雪旺细胞在周围神经的生理冲动传导中起着至关重要的作用。它们产生髓磷脂，提供轴突代谢支持，并参与神经损伤后的修复过程。在衰老过程中，周围神经获得髓鞘结构异常，其特征是SC的比例较低，衰老细胞的比例较高。所有这些变化都与电传导受损相关，从而改变靶组织的功能，包括骨骼肌无力和心律失常。为了表征和比较心脏和坐骨神经SC，以及探索SC丰度的年龄相关差异及其特性，我们分析了两种TdTomato报告小鼠菌株，分离出表达Sox10或Plp1的SC。我们对从心脏和坐骨神经中分离出来的TdTomato阳性细胞进行了rna测序，并在蛋白水平上使用免疫荧光验证转录组学结果。我们的数据显示，与坐骨SC相比，心脏SC中有促血管生成的特征。此外，与年轻小鼠相比，老年小鼠的心脏SC中检测到较高水平的神经死亡相关基因和较低水平的脂肪酸共转运蛋白Fabp4/ Fabp4的基因和蛋白表达，这表明衰老相关的脂肪酸转运损伤。最后，坐骨SC激活胶原重塑，增加促炎信号，包括TNFα。因此，心脏和肌肉骨骼SC具有不同的表达谱，并在衰老过程中经历不同的变化，这可能导致两个器官系统的神经功能受损。

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引用次数: 0

Myofibroblast specific knockdown of NSUN2 suppresses cardiac fibrosis post-myocardial infarction 肌成纤维细胞特异性敲低NSUN2可抑制心肌梗死后的心肌纤维化。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-10-02 DOI: 10.1016/j.yjmcc.2025.09.009

Zhiyong Sun , Na Li , Min Huang , Ying Li , Changhao Wang , Zhezhe Qu , Shuting Yu , Zhongting Mei , Bo Wu , Shunkang Dou , Jianhao Jiang , Yaozhi Zhang , Chuanhao Huang , Jiaqi Han , Yufei Yue , Xin Li , Yuechao Dong , Weijie Du

Cardiac fibrosis, a common pathological process characterized by excessive deposition of extracellular matrix components in the myocardium, poses a critical challenge in the field of cardiovascular research and clinical practice. 5-Methylcytosine (m5C) is an extensive post-transcriptional RNA modification known to participate in various cellular responses and biological processes by regulating RNA metabolism. However, it remains unclear whether m5C RNA modifications exert regulatory effects on cardiovascular diseases, particularly cardiac fibrosis. Here, we report that NSUN2, a typical m5C methyltransferase, affects the RNA stability of HuR through m5C modification, promoting the development of cardiac fibrosis. Upon the conditional knockdown of NSUN2 specifically in myofibroblasts, the extent of cardiac fibrosis was suppressed. In conclusion, we specifically knocked down NSUN2 in cardiac myofibroblasts, which further reduced the RNA stability of HuR and thus ameliorated cardiac fibrosis caused by myocardial ischemia, offering a new therapeutic target for the clinical treatment of cardiac fibrosis.

心脏纤维化是一种以心肌细胞外基质成分过度沉积为特征的常见病理过程，是心血管研究和临床实践领域的重要挑战。5-甲基胞嘧啶（m5C）是一种广泛的转录后RNA修饰，通过调节RNA代谢参与各种细胞反应和生物学过程。然而，目前尚不清楚m5C RNA修饰是否对心血管疾病，特别是心脏纤维化具有调节作用。在这里，我们报道了典型的m5C甲基转移酶NSUN2通过m5C修饰影响HuR的RNA稳定性，促进心脏纤维化的发展。在肌成纤维细胞中特异性地条件敲低NSUN2后，心脏纤维化程度受到抑制。总之，我们在心肌成纤维细胞中特异性敲低NSUN2，进一步降低HuR的RNA稳定性，从而改善心肌缺血引起的心脏纤维化，为临床治疗心脏纤维化提供了新的治疗靶点。

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引用次数: 0

Animal models and mechanisms of exercise in attenuating cardiac injury induced by beta-adrenergic hyperactivation 运动减轻β -肾上腺素能过度激活引起的心脏损伤的动物模型和机制。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-09-30 DOI: 10.1016/j.yjmcc.2025.09.007

Yong Peng , Linlin Shang , Gan Chen , Simeng Zhao , Mengyun Mao , Danxi Zhu , Di Qin

Acute sympathetic stress, which causes hyperactivation of β-adrenergic receptors (β-AR) in the heart, is a key pathological factor in the development of cardiac disease. Isoproterenol (ISO) is a non-selective β-AR agonist, which was utilized to develop an experimental animal model of pathological cardiac remodeling, simulating the acute sympathetic stress-induced cardiac injury. Current research evidences support the potential role of exercise in preventing or treating heart injury caused by β-adrenergic overactivation. The mechanisms of exercise against ISO-induced cardiac injury include of inhibiting cardiac inflammation and oxidative stress, suppressing apoptosis, pyroptosis, and necroptosis in cardiomyocytes, activating Adenosine 5′ -monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, reducing reactive oxygen species (ROS) to regulate the inflammatory response. Despite the protective effects of exercise in attenuating ISO-induced cardiac injury, further studies are necessary to explore the optimal combination of exercise intensity and duration. Additionally, comparative research is required to evaluate the protective effects of different exercise types, investigate the relationship between exercise-induced protection and ISO dosage, and reveal new mechanism underlying the protective effects of exercise against ISO-induced heart injury. This study will improve our understanding of the mechanisms by which exercise protects against cardiac injury induced by β-adrenergic overload, and establish a stronger foundation for studying the effects of exercise against β-adrenergic overload-induced cardiac injury.

急性交感应激引起心脏β-肾上腺素能受体（β-AR）的过度激活，是心脏病发生的关键病理因素。异丙肾上腺素（isoterenol， ISO）是一种非选择性β-AR激动剂，用于建立病理性心脏重构的实验动物模型，模拟急性交感应激性心脏损伤。目前的研究证据支持运动在预防或治疗β-肾上腺素能过度激活引起的心脏损伤中的潜在作用。运动对抗iso诱导的心脏损伤的机制包括抑制心脏炎症和氧化应激，抑制心肌细胞凋亡、焦亡和坏死，激活腺苷5′-单磷酸腺苷（AMP）活化蛋白激酶（AMPK）信号通路，减少活性氧（ROS）调节炎症反应。尽管运动对减轻iso引起的心脏损伤有保护作用，但需要进一步研究运动强度和运动时间的最佳组合。此外，还需要进行比较研究，评估不同运动类型的保护作用，探讨运动诱导的保护作用与ISO剂量的关系，揭示运动对ISO诱导的心脏损伤保护作用的新机制。本研究将提高我们对运动对β-肾上腺素能负荷引起的心脏损伤的保护机制的认识，并为研究运动对β-肾上腺素能负荷引起的心脏损伤的作用奠定更坚实的基础。

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引用次数: 0

Decoding long COVID-associated cardiovascular dysfunction: Mechanisms, models, and new approach methodologies 解码长期与covid - 19相关的心血管功能障碍：机制、模型和新方法方法。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-09-30 DOI: 10.1016/j.yjmcc.2025.09.008

Dilip Thomas , Phillip C. Yang , Joseph C. Wu , Nazish Sayed

The COVID-19 pandemic has revealed that the impact of SARS-CoV-2 infection extends well beyond the acute phase, with long-term sequelae affecting multiple organ systems, most notably, the cardiovascular system. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by persistent symptoms such as fatigue, dyspnea, chest pain, and palpitations, which can last for months or even years after initial recovery. Increasing evidence implicates immune dysregulation, endothelial dysfunction, persistent viral antigens, and coagulopathy as central drivers of cardiovascular complications. Mechanistic studies demonstrate that direct viral infection of cardiac and vascular cells, along with autoantibody formation and cytokine-mediated injury, contribute to myocardial inflammation, fibrosis, and arrhythmias. Sex-based immunological differences and underlying comorbidities further influence individual susceptibility and disease trajectory. Large-scale epidemiological studies have confirmed significantly increased risks of pericarditis, cardiomyopathy, dysrhythmias, and heart failure among COVID-19 survivors. In parallel, the emergence of advanced preclinical platforms, including patient-derived induced pluripotent stem cell (iPSC)-based cardiac organoids, engineered heart tissues, and organ-on-a-chip systems has enabled mechanistic dissection of Long COVID pathophysiology. These human-relevant models, when integrated with clinical datasets and artificial intelligence (AI)-driven analytics, offer powerful tools for biomarker discovery, risk stratification, and precision therapeutic development. This review synthesizes the current understanding of cardiovascular involvement in Long COVID, highlights key mechanistic insights from both clinical and preclinical studies, and outlines future directions for diagnostic and therapeutic innovation.

COVID-19大流行表明，SARS-CoV-2感染的影响远远超出急性期，其长期后遗症会影响多器官系统，尤其是心血管系统。长冠状病毒，或SARS-CoV-2感染的急性后后遗症（PASC），其特征是持续症状，如疲劳、呼吸困难、胸痛和心悸，这些症状在最初恢复后可能持续数月甚至数年。越来越多的证据表明，免疫失调、内皮功能障碍、持久性病毒抗原和凝血功能障碍是心血管并发症的主要驱动因素。机制研究表明，心脏和血管细胞的直接病毒感染，以及自身抗体的形成和细胞因子介导的损伤，有助于心肌炎症、纤维化和心律失常。基于性别的免疫差异和潜在的合并症进一步影响个体易感性和疾病轨迹。大规模流行病学研究证实，COVID-19幸存者患心包炎、心肌病、心律失常和心力衰竭的风险显著增加。与此同时，先进的临床前平台的出现，包括基于患者来源的诱导多能干细胞（iPSC）的心脏类器官、工程化心脏组织和器官芯片系统，使长冠状病毒病理生理学的机械解剖成为可能。这些与人类相关的模型与临床数据集和人工智能（AI）驱动的分析相结合，为生物标志物发现、风险分层和精确治疗开发提供了强大的工具。这篇综述综合了目前对长冠状病毒病心血管参与的理解，强调了临床和临床前研究的关键机制见解，并概述了诊断和治疗创新的未来方向。

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引用次数: 0

Targeting the NLRP3 Inflammasome-Gasdermin D Axis to Combat Cardiovascular Diseases 靶向NLRP3炎性小体-气皮蛋白D轴对抗心血管疾病

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-09-23 DOI: 10.1016/j.yjmcc.2025.09.006

Judy S. Choi , Mehnaz Pervin , James E. Vince , Arpeeta Sharma , Judy B. de Haan

Cardiovascular disease remains a leading global cause of mortality, with inflammation playing a crucial role in driving its pathology. Despite advancements in cardiovascular disease management, current treatment options primarily address risk factors and symptoms rather than underlying disease mechanisms. Among the key mechanistic drivers are the NLRP3 multiprotein inflammasome complexes of the innate immune system, which are activated in response to cellular stress or injury. One of the key downstream effectors of NLRP3 activation is gasdermin D, which forms pores in the plasma membrane to initiate pyroptotic cell death, leading to the release of pro-inflammatory cytokines. This review will highlight the role of NLRP3 inflammasome activation and gasdermin D-mediated pyroptosis in driving cardiovascular diseases, including atherosclerosis, myocardial infarction, ischemic stroke and diabetic cardiomyopathy. It will also identify recent innovative therapeutic approaches that target the NLRP3 inflammasome-gasdermin D axis, which are currently being evaluated in preclinical studies and clinical trials.

心血管疾病仍然是全球主要的死亡原因，炎症在其病理过程中起着至关重要的作用。尽管心血管疾病管理取得了进步，但目前的治疗方案主要针对风险因素和症状，而不是潜在的疾病机制。其中关键的机制驱动因素是先天免疫系统的NLRP3多蛋白炎性体复合物，它在细胞应激或损伤的反应中被激活。NLRP3激活的关键下游效应物之一是气真皮蛋白D，它在质膜上形成孔隙，引发热腐细胞死亡，导致促炎细胞因子的释放。本文将重点介绍NLRP3炎性体激活和气皮蛋白d介导的焦亡在心血管疾病中的作用，包括动脉粥样硬化、心肌梗死、缺血性卒中和糖尿病性心肌病。它还将确定针对NLRP3炎症小体-气皮蛋白D轴的最新创新治疗方法，这些方法目前正在临床前研究和临床试验中进行评估。

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引用次数: 0

SMYD1-mediated mono-methylation of lysine K35 of sarcomeric myosin heavy chain (MHC) regulates sarcomere assembly and homeostasis in zebrafish and human iPSC-derived cardiomyocytes smyd1介导的肌球蛋白重链（MHC）赖氨酸K35的单甲基化调节斑马鱼和人类ipsc来源的心肌细胞的肌小体组装和稳态。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-09-17 DOI: 10.1016/j.yjmcc.2025.09.002

Federica Diofano , Chidinma Amadi , Larissa Hartmann , Bernd M. Gahr , Karolina Weinmann-Emhardt , Wolfgang Rottbauer , Steffen Just

The SMYD family comprises a distinct class of lysine methyltransferases (KMTases) that methylate both histone and non-histone proteins. Among its five members (SMYD1–5), SMYD1 has been identified as a cardiac and skeletal muscle-specific KMTase that interacts with Myosin, in coordination with Unc45b and Hsp90a, to regulate thick filament assembly. However, the precise mechanism by which SMYD1 orchestrates Myosin assembly remains largely unknown.

Here, we demonstrate that SMYD1 physically associates with the N-terminal region of several myosin heavy chain (MyHC) isoforms and specifically catalyzes the mono-methylation of MyHC at lysine 35 (K35). Methylated MyHC is correctly incorporated into sarcomeres, whereas unmethylated MyHC in Smyd1-deficient zebrafish undergoes degradation via the ubiquitin-proteasome system (UPS), leading to defective thick filament assembly. Although UPS inhibition with MG132 restores Myosin levels in Smyd1-deficient zebrafish embryos, proper thick filament assembly remains impaired due to the absence of K35 MyHC mono-methylation.

Similar to zebrafish striated muscle cells, SMYD1-mediated MyHC methylation is essential for thick filament assembly but also homeostasis in human cardiomyocytes, indicating a conserved cross-species mechanism of Myosin regulation, first described nearly 40 years ago. Further research is now required to explore the therapeutic potential of targeting this pathway in cardiomyopathies and skeletal muscle disorders.

SMYD家族包括一种独特的赖氨酸甲基转移酶（KMTases），可将组蛋白和非组蛋白甲基化。在其5个成员（SMYD1-5）中，SMYD1已被确定为心脏和骨骼肌特异性KMTase，与Myosin相互作用，与Unc45b和Hsp90a协调，调节粗丝组装。然而，SMYD1协调肌球蛋白组装的确切机制在很大程度上仍然未知。在这里，我们证明SMYD1与几种肌球蛋白重链（MyHC）亚型的n端区域物理结合，并特异性催化MyHC在赖氨酸35 （K35）的单甲基化。甲基化的MyHC被正确地整合到肌瘤中，而在smyd1缺陷的斑马鱼中，未甲基化的MyHC通过泛素-蛋白酶体系统（UPS）进行降解，导致粗丝组装缺陷。尽管使用MG132抑制UPS可以恢复smyd1缺陷斑马鱼胚胎中的肌球蛋白水平，但由于缺乏K35 MyHC单甲基化，适当的粗丝组装仍然受到损害。与斑马鱼横纹肌细胞类似，smyd1介导的MyHC甲基化对于粗丝组装和人类心肌细胞的内稳态至关重要，这表明Myosin调节的保守跨物种机制在近40 年前首次被描述。现在需要进一步的研究来探索靶向这一途径在心肌病和骨骼肌疾病中的治疗潜力。

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