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

FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil's proatherogenic phenotype which is modulated by semaglutide FABP4是心血管疾病预后不良的标志，可诱导嗜中性粒细胞的促动脉粥样硬化表型，并受semaglutide调节。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.yjmcc.2025.10.009

David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras

Dysfunctional epicardial adiposity is a risk factor for coronary artery disease (CAD). Its genesis is associated with an upregulation of fatty acid binding protein 4 (FABP4) levels, which might exert paracrine inflammatory and atherogenic mechanisms on the cardiovascular system. We aimed to study the prognosis of patients with high systemic FABP4, its association with a neutrophil proatherogenic phenotype, involved mechanisms and its modulation by semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1ra). Higher plasma FABP4 levels than 50 ng/mL were associated with heart failure (HF) onset during follow-up. In patients with CAD, these levels were associated with pro-inflammatory and pro-atherogenic neutrophil profile markers as MPO, NGAL and CD11b, analysed by real-time PCR. The group of patients with the highest FABP4 levels exhibited higher levels of MMP9, CXCR2, and CD11b in neutrophils. A preclinical model, based on neutrophils and coronary endothelial cells, determined the effects of FABP4 on neutrophils' respiratory burst, by flow cytometry, activity of NF-κΒ, by western blot checking IκΒα phosphorylation, CD11b integrin expression levels and adhesion to coronary endothelial cells. A modulation of the neutrophils' transcriptome, analysed by RNA-seq, and plasma chemokine CCL5 levels suggested changes in leukocyte migration and platelet activation pathways in patients who reduced plasma FABP4 levels after semaglutide treatment. Thus, supraphysiological levels of FABP4 induce pro-inflammatory and proatherogenic mechanisms in neutrophils and coronary endothelial cells. Its modulation by semaglutide could explain its benefits on coronary artery disease (CAD).

功能失调的心外膜脂肪是冠状动脉疾病（CAD）的危险因素。它的发生与脂肪酸结合蛋白4 （FABP4）水平的上调有关，这可能在心血管系统中发挥旁分泌炎症和动脉粥样硬化机制。我们的目的是研究高系统性FABP4患者的预后，其与中性粒细胞促动脉粥样硬化表型的关系，涉及的机制及其通过胰高血糖素样肽-1受体激动剂（GLP-1ra）的调节。随访期间，血浆FABP4水平高于50 ng/mL与心力衰竭（HF）发病相关。在CAD患者中，通过实时PCR分析，这些水平与促炎和促动脉粥样硬化中性粒细胞谱标记物MPO、NGAL和CD11b相关。FABP4水平最高的患者组表现出中性粒细胞中MMP9、CXCR2和CD11b水平较高。建立以中性粒细胞和冠状动脉内皮细胞为基础的临床前模型，通过流式细胞术、NF活性-κΒ、western blot检测IκΒα磷酸化、CD11b整合素表达水平和冠状动脉内皮细胞粘附，检测FABP4对中性粒细胞呼吸爆发的影响。通过RNA-seq分析中性粒细胞转录组的调节和血浆趋化因子CCL5水平表明，在半马鲁肽治疗后血浆FABP4水平降低的患者中，白细胞迁移和血小板激活途径发生了变化。因此，超生理水平的FABP4诱导中性粒细胞和冠状动脉内皮细胞的促炎和促动脉粥样硬化机制。西马鲁肽对其的调节可以解释其对冠心病（CAD）的益处。

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引用次数: 0

Cardiac fibroblasts-specific USP7 drives post-infarction cardiac fibrosis by deubiquitinating Krüppel-like factor 7 to promote myofibroblast activation 心肌成纤维细胞特异性USP7通过去泛素化kr<e:1>样因子7促进肌成纤维细胞活化来驱动梗死后心肌纤维化。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-12 DOI: 10.1016/j.yjmcc.2025.11.001

Jie Yang , Shaopeng Cheng , Hoshun Chong , Qiuyan Zong , Yilin Wang , Tingting Tong , Yi Jiang , Jian Shi , Ronghuang Yu , Xiujuan Cai , Hanqing Luo , Hao Chen , Chuiyu Kong , Yunxing Xue , Dongjin Wang

Although cardiac fibroblast-to-myofibroblast transition (FMT) can critically exacerbate collagen deposition and adverse remodeling after myocardial infarction (MI), the underlying regulatory mechanisms remains unclear. While ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, has been implicated in cardiomyocyte ischemia injury, its role in myofibroblast transition following MI is unknown. Here, we identify cardiac fibroblasts-specific USP7 as a key mediator of FMT and fibrosis. USP7 expression was upregulated in infarcted murine hearts and isolated cardiac fibroblasts, and the upregulated expression was correlated with human fibrotic myocardium. Silencing of USP7 expression suppressed transforming growth factor (TGF)-β1-induced FMT and reduced the expression of

α

-SMA. In comparison with the findings in USP7^flox/flox mice, specific knockout of USP7 in cardiac fibroblasts and in myofibroblasts greatly attenuated fibrotic remodeling and ventricular dysfunction post-MI. Mechanistically, USP7 directly bound to Krüppel-like factor 7 (KLF7) through the N-terminal tumor necrosis factor receptor-associated factor (TRAF)-like domain, causing deubiquitination of KLF7. Cysteine at position 223 (C223) of USP7 induced K48 deubiquitination to promote KLF7 nuclear accumulation, thereby facilitating transcription of GATA3 by directly binding to the GATA3 promoter to induce the expression of pro-fibrosis genes. Adeno-associated virus 9 (AAV9)-mediated USP7 overexpression worsened systolic dysfunction and adverse remodeling. The protective effects of USP7 knockout were abolished by KLF7 overexpression. Our results indicate that USP7 contributes to FMT, thereby aggravating adverse remodeling and cardiac dysfunction by deubiquitinating KLF7 post-MI. Our findings characterize the USP7-KLF7-GATA3 axis as a novel regulator of FMT and propose fibroblast USP7 as a therapeutic target for post-MI remodeling.

尽管心肌成纤维细胞向肌成纤维细胞转化（FMT）可严重加剧心肌梗死（MI）后的胶原沉积和不良重构，但其潜在的调节机制尚不清楚。虽然泛素特异性蛋白酶7 （USP7）是一种去泛素化酶，与心肌细胞缺血损伤有关，但其在心肌梗死后肌成纤维细胞转化中的作用尚不清楚。在这里，我们发现心脏成纤维细胞特异性USP7是FMT和纤维化的关键介质。USP7在梗死小鼠心脏和离体心脏成纤维细胞中表达上调，且上调表达与人纤维化心肌相关。沉默USP7表达可抑制转化生长因子(TGF)-β1诱导的FMT，降低α-SMA的表达。与USP7flox/flox小鼠的研究结果相比，在心肌成纤维细胞和肌成纤维细胞中特异性敲除USP7可大大减轻心肌梗死后的纤维化重塑和心室功能障碍。机制上，USP7通过n端肿瘤坏死因子受体相关因子（TRAF）样结构域直接与kr ppel样因子7 （KLF7）结合，导致KLF7去泛素化。USP7 223位（C223）半胱氨酸诱导K48去泛素化，促进KLF7核积累，从而通过直接结合GATA3启动子促进GATA3转录，诱导促纤维化基因表达。腺相关病毒9 （AAV9）介导的USP7过表达加重了收缩功能障碍和不良重构。KLF7过表达可消除USP7敲除的保护作用。我们的研究结果表明，USP7有助于FMT，从而通过去泛素化KLF7加重心肌梗死后的不良重塑和心功能障碍。我们的研究结果将USP7- klf7 - gata3轴描述为FMT的一种新的调节因子，并提出成纤维细胞USP7作为心肌梗死后重构的治疗靶点。

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引用次数: 0

Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis 小规模siRNA筛选显示WWC2是心肌细胞有丝分裂的一种新的调节因子。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-15 DOI: 10.1016/j.yjmcc.2025.11.004

Dogacan Yücel , Calvin Smith , Natalia Ferreira de Araujo , Fernando Souza-Neto , Upendra Chalise , Grace Schuler , Bayardo I. Garay , Jennifer L. Mikkila , Omar Atef Abdelhamid Mahmoud , Pratima Mandal , Rita C.R. Perlingeiro , Jop H. van Berlo

Summary (145)

Adult cardiomyocytes exit the cell cycle soon after birth, although this shift can be reversed by molecular interventions. To identify novel regulators of cardiomyocyte proliferation, we performed a comparative transcriptomic analysis of actively proliferating and non-proliferating cardiomyocytes across key pre-and post-natal developmental timepoints. Integration of bioinformatics analyses with a functional screen of 238 differentially expressed genes identified WWC2 as a regulator of cell cycle exit. Inhibition of Wwc2 induced cell cycle entry with completion of mitosis and cytokinesis, while overexpression of WWC2 induced cell cycle exit. Moreover, inhibition of Wwc2 resulted in dedifferentiation of cardiomyocytes with reduced expression of sarcomeric and calcium handling genes. Mechanistically, WWC2 binds to 14–3-3 and regulates YAP phosphorylation and expression. In vivo, deletion of Wwc2 stimulated cardiac regeneration after myocardial infarction. These results identify WWC2 as an important regulator of cardiomyocyte cell cycle exit and initiation of the maturation process.

成人心肌细胞在出生后不久就退出细胞周期，尽管这种转变可以通过分子干预来逆转。为了确定心肌细胞增殖的新调控因子，我们在关键的产前和产后发育时间点对活跃增殖和非增殖心肌细胞进行了比较转录组学分析。将生物信息学分析与238个差异表达基因的功能筛选相结合，确定WWC2是细胞周期退出的调节因子。抑制Wwc2诱导细胞周期进入并完成有丝分裂和细胞质分裂，而过表达Wwc2诱导细胞周期退出。此外，Wwc2的抑制导致心肌细胞去分化，并减少肌合成和钙处理基因的表达。机制上，WWC2结合14-3-3调控YAP磷酸化和表达。在体内，Wwc2的缺失刺激心肌梗死后的心脏再生。这些结果表明WWC2是心肌细胞周期退出和成熟过程开始的重要调节因子。

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引用次数: 0

The long non-coding RNA Snhg15 protects the heart after myocardial infarction 长链非编码RNA Snhg15保护心肌梗死后的心脏。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1016/j.yjmcc.2025.10.011

Mariana Shumliakivska , Ariane Fischer , Marion Muhly-Reinholz , Vincent Elvin Leonard , Tina Rasper , Galip S. Aslan , Yosif Manavski , Julian U.G. Wagner , Benjamin Meder , Susanne S. Hille , Oliver J. Müller , Guillermo Luxán , Stefanie Dimmeler

Cardiomyocytes are postmitotic cells that do not proliferate in the heart. In order to maintain the structural integrity of the heart, cardiomyocyte loss due to cell death after myocardial infarction is compensated with a non-contractile fibrotic scar that compromises cardiac function. Here, we have combined heart failure transcriptomics with in vitro assays to determine the molecular mechanisms that govern cell death in heart failure. Our data identified the reduced gene expression of the long non-coding RNA (lncRNA) small nucleolar RNA host gene 15 (Snhg15) as a hallmark of ischemic and dilated heart failure. Furthermore, loss-of-function studies in HL-1-cardiomyocyte-like cells revealed that Snhg15 depletion induces nucleolar disruption and cell death in a p53-dependent mechanism. Finally, adeno-associated virus delivery of Snhg15 prior to a myocardial infarction partially protected cardiac function in the acute and chronic phases after myocardial infarction. In conclusion, our studies identify Snhg15 as a regulator of cardiomyocyte cell death in the context of heart failure and suggest that delivery of the lncRNA may represent a potential therapeutic tool to reduce cardiomyocyte death.

心肌细胞是有丝分裂后的细胞，在心脏中不会增殖。为了维持心脏的结构完整性，心肌梗死后细胞死亡导致的心肌细胞损失由损害心功能的非收缩性纤维化疤痕来补偿。在这里，我们将心力衰竭转录组学与体外测定相结合，以确定心力衰竭中控制细胞死亡的分子机制。我们的数据表明，长链非编码RNA （lncRNA）小核仁RNA宿主基因15 （Snhg15）的基因表达降低是缺血性和扩张性心力衰竭的标志。此外，对hl -1心肌细胞样细胞的功能丧失研究表明，Snhg15缺失以p53依赖的机制诱导核仁破坏和细胞死亡。最后，心肌梗死前腺相关病毒递送Snhg15部分保护心肌梗死后急性期和慢性期的心功能。总之，我们的研究确定了Snhg15在心力衰竭的情况下是心肌细胞死亡的调节因子，并提示lncRNA的递送可能是减少心肌细胞死亡的潜在治疗工具。

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引用次数: 0

Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1 可溶性环氧化物水解酶缺乏症通过靶向细胞色素P450 2E1挽救心力衰竭并保留射血分数。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-15 DOI: 10.1016/j.yjmcc.2025.11.005

Min Zhang , Chen Chen , Xinxing Liu , Zhou Zhou , Gen Li , Xiangrui Jiang , Jingshan Shen , Hualiang Jiang , Zheng Wen , Yan Liu , Dao Wen Wang

Background

Our prior clinical studies established a positive correlation between sEH activity and mortality in heart failure with preserved ejection fraction (HFpEF), the pathophysiological role of the sEH/EET axis in metabolic stress (obesity and metabolic syndrome) and mechanical stress (hypertension)-induced HFpEF remains unknown.

Methods

We elucidated the function and mechanism of sEH and EETs in ‘two-hit’ (high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitrol-arginine methyl ester) HFpEF animal model. Langendorff system was applied to isolate cardiomyocytes from HFpEF mice. Recombinant adeno-associated virus type 9 was used to deliver cytochrome P450 2E1 (CYP2E1) to cardiac-specific knockout sEH HFpEF mice through the tail vein.

Results

sEH activity and expression were upregulated, while EETs levels were reduced in the hearts and isolated cardiomyocytes from HFpEF mice or cardiomyocyte cell lines pretreated with palmitate acid and Nω-nitrol-arginine methyl ester. Desuccinylation, a posttranslational modification of sEH (K)¹⁹¹, maintained the activity of sEH in HFpEF. Genetic or pharmacological inhibition of the sEH restored the levels of EETs and ameliorated HFpEF phenotype with significantly improved diastolic dysfunction and cardiac remodeling. Mechanically, sEH inhibitors (sEHIs) targeted CYP2E1, a crucial CYP450 enzyme, to inhibit reactive oxygen species (ROS) and fatty acid uptake. Overexpressing CYP2E1 abolished the protective effects of sEH inhibition in vivo.

Conclusions

These findings confirmed sEH as a therapeutic target in metabolic stress and mechanical stress-induced HFpEF mice model via the cardioprotective effects of EETs, which were mediated partially by targeting CYP2E1, suggesting the development of therapeutic strategies for patients with HFpEF.

背景：我们之前的临床研究证实了sEH活性与保留射血分数（HFpEF）心力衰竭患者死亡率之间的正相关，但sEH/EET轴在代谢应激（肥胖和代谢综合征）和机械应激（高血压）诱导的HFpEF中的病理生理作用尚不清楚。方法：采用ω-硝基精氨酸甲酯（n ω-硝基精氨酸甲酯）HFpEF动物模型，研究sEH和EETs在高脂饮食和抑制组成型一氧化氮合酶的“双打击”模型中的作用和机制。采用Langendorff系统分离HFpEF小鼠心肌细胞。利用重组腺相关病毒9型通过尾静脉将细胞色素P450 2E1 （CYP2E1）传递给心脏特异性敲除sEH的HFpEF小鼠。结果：经棕榈酸和n ω-硝基精氨酸甲酯预处理的HFpEF小鼠或心肌细胞系的心脏和离体心肌细胞中sEH活性和表达上调，EET水平降低。sEH (K)191的翻译后修饰去琥珀酰化维持了HFpEF中sEH的活性。遗传或药物抑制sEH恢复EETs水平，改善HFpEF表型，显著改善舒张功能障碍和心脏重塑。机械上，sEH抑制剂（sEHIs）靶向CYP2E1（一种关键的CYP450酶）来抑制活性氧（ROS）和脂肪酸的摄取。体内过表达CYP2E1可消除sEH抑制的保护作用。结论：这些发现证实了sEH是代谢应激和机械应激诱导的HFpEF小鼠模型的治疗靶点，EETs的心脏保护作用部分是通过靶向CYP2E1介导的，提示了HFpEF患者治疗策略的发展。

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引用次数: 0

IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia IGF-1促进HCN4起搏器通道的细胞表面表达，促进心动过速。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-01 DOI: 10.1016/j.yjmcc.2025.10.015

Nadine Erlenhardt , Franziska Wohlfarth , S. Erfan Moussavi-Torshizi , Angela Koch , Tobias Strasdeit , Katharina Scherschel , Ehsan Amin , Max Anstötz , Christian Meyer , Nikolaj Klöcker

Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an ex vivo mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in Xenopus laevis oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.

胰岛素样生长因子1 （IGF-1）控制心脏生长、代谢和收缩性。虽然IGF-1缺乏与心血管风险相关，但其信号转导的激活可能在急性心肌梗死后具有心脏保护作用。临床研究评估了全身性IGF-1在包括心力衰竭在内的疾病中的治疗潜力，并报道了作为常见副作用的心动过速。在这里，我们证明了IGF-1在体外小鼠窦房结准备中加速了心脏起搏。结合细胞外表位标记和电生理学在非洲爪蟾卵母细胞中进行的异源重构实验显示，IGF-1增加了心脏起搏器主要通道异构体HCN4的细胞表面表达，从而刺激了依赖rab11的通道蛋白的内体再循环。总之，该研究不仅增加了HCN通道通过生长因子信号调节的模式，而且可能扩展了我们对心律失常的理解，心律失常通常是由IGF-1失调引起的，包括心脏肥厚。

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引用次数: 0

Slit2-robo signaling regulates angiogenesis and repair following myocardial infarction Slit2-robo信号调控心肌梗死后血管生成和修复。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-05 DOI: 10.1016/j.yjmcc.2025.10.014

David Wong , Matthew Tran , Julie Martinez , Itzetl Avila , Adrian Arrieta , Kyle Kalindjian , Elle Rathbun , Thomas M. Vondriska , Eric M. Small , Pearl Quijada

The Slit2 guidance ligand and its Roundabout (Robo) family of receptors regulate axonal guidance and vascular patterning during cardiac morphogenesis, yet the role of Slit2-Robo signaling in the adult heart remains unclear. Here, we identified epicardium-derived Slit2 as highly enriched in neonatal cardiac fibroblasts (cFBs) but markedly reduced in adult hearts. Following myocardial infarction (MI), Slit2 transiently increases in the infarct border zone seven days post-MI but declines significantly after one month. In vitro, Slit2 overexpression in cFBs selectively upregulated angiogenic genes during myofibroblast differentiation without affecting extracellular matrix (ECM) gene expression. In vivo, AAV9-mediated cardiac-specific overexpression of Slit2 (AAV9-cTNT-Slit2) improved cardiac function, increased endothelial cell (EC) proliferation and vascular density, but did not alter fibrotic deposition following MI. Conditioned media from Slit2-overexpressing cFBs promoted EC proliferation, activation, and tube forming abilities, consistent with the increased expression of pro-angiogenic Robo1 and other vascular growth factors in the myocardium of AAV9-Slit2-treated hearts. Additionally, Slit2 overexpression attenuated cardiomyocyte hypertrophy after MI and suppressed fetal gene expression in vitro. Mechanistically, Slit2 appears to mediate its cardioprotective effects through enhanced interactions with Robo1 in cFBs and ECs. These findings support Slit2-Robo signaling as a promising therapeutic target for improving blood vessel formation and maintaining cardiac muscle integrity following ischemic injury.

Slit2引导配体及其Roundabout （Robo）受体家族在心脏形态发生过程中调节轴突引导和血管模式，但Slit2-Robo信号在成人心脏中的作用尚不清楚。在这里，我们发现心外膜衍生的Slit2在新生儿心脏成纤维细胞（cfb）中高度富集，但在成人心脏中明显减少。心肌梗死（MI）后7天，Slit2在梗死边界区短暂升高，1个月后显著下降。在体外，cFBs中Slit2的过表达在肌成纤维细胞分化过程中选择性上调血管生成基因，而不影响细胞外基质（ECM）基因的表达。在体内，aav9介导的心脏特异性过表达的Slit2 （AAV9-cTNT-Slit2）改善了心功能，增加了内皮细胞（EC）的增殖和血管密度，但没有改变心肌梗死后的纤维化沉积。从Slit2过表达的cFBs中获得的条件培养基促进了EC的增殖、活化和成管能力，这与aav9 -Slit2处理的心脏心肌中促血管生成的Robo1和其他血管生长因子的表达增加一致。此外，在体外实验中，Slit2过表达可减轻心肌梗死后心肌细胞肥大，抑制胎儿基因表达。在机制上，Slit2似乎通过在cfb和ECs中增强与Robo1的相互作用来调节其心脏保护作用。这些发现支持Slit2-Robo信号作为缺血性损伤后改善血管形成和维持心肌完整性的有希望的治疗靶点。

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引用次数: 0

PhysioMEA: Signal processing platform for rate and rhythm analysis of multi-electrode array cardiac electrophysiological recordings PhysioMEA：多电极阵列心脏电生理记录的频率和节律分析信号处理平台。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-01 Epub Date: 2025-11-17 DOI: 10.1016/j.yjmcc.2025.11.006

Ido Weiser-Bitoun , Savyon Mazgaoker , Shani Assayag , Moran Davoodi , Alexandra Alexandrovich , Yael Yaniv

Cardiac organoids serve as a valuable model for studying physiological and pathophysiological processes affecting heart rate and rhythm. Multi-electrode arrays (MEA) are widely used for high-throughput electrophysiological assessments. Despite the widespread use of MEA technology in cardiac research, current analysis tools primarily focus on one dimensional (1D) electrophysiological biomarkers and on average interbeat intervals.

We aim to develop innovative algorithms to expand cardiac electrophysiological analysis by enabling standardized biomarker calculation, spatiotemporal biomarker dynamics assessment, and comprehensive beat rate variability (BRV) analysis of cardiac organoids.

Electrograms were recorded from spontaneously beating cardiac organoids (n = 15), generated from human-induced pluripotent stem cell-derived cardiomyocytes, using 8 × 8 electrode MEA plates. Novel algorithms were developed for R-, S-, and T-peak detection, as well as advanced two dimensions (2D) electrical signal processing of these biomarkers. All algorithms were implemented on the PhysioMEA platform.

Biomarker distributions in cardiac organoids exhibited a high degree of similarity in 1D under basal conditions, as indicated by their coefficients of variation (p-value >0.209). In 2D, R- to S-peaks amplitude, maximal slope, peak-to-peak duration and field potential duration coefficients of variation were 39.04 %, 46.95 %, 22.76 %, and 25.00 %, respectively. Additionally, comprehensive analysis of BRV revealed primarily very low frequency content (63.42 %) in cardiac organoid interbeat interval spectra compared to low- and high-frequency components (15.57 % and 21.02 %, respectively).

Thus, 1D and 2D electrophysiological analysis and BRV assessment of cardiac organoids using the open-source PhysioMEA platform, shows high similarities in 1D, but not in 2D, between different physiological biomarkers.

心脏类器官是研究影响心率和节律的生理和病理生理过程的一个有价值的模型。多电极阵列（MEA）被广泛用于高通量电生理评估。尽管MEA技术在心脏研究中被广泛使用，但目前的分析工具主要集中在一维（1D）电生理生物标志物和平均心跳间隔上。我们的目标是通过标准化的生物标志物计算、时空生物标志物动力学评估和心脏类器官的综合心率变异性（BRV）分析，开发创新的算法来扩展心脏电生理分析。使用8个 × 8电极MEA板记录由人诱导的多能干细胞衍生的心肌细胞产生的自发跳动的心脏类器官（n = 15）的电图。研究人员开发了R、S和t峰检测的新算法，以及这些生物标志物的先进二维（2D）电信号处理。所有算法均在PhysioMEA平台上实现。从变异系数（p值>0.209）可以看出，在基础条件下，心脏类器官中生物标志物的分布在1D中表现出高度的相似性。在2D中，R- s峰振幅、最大斜率、峰间持续时间和场电位持续时间变异系数分别为39.04 %、46.95 %、22.76 %和25.00 %。此外，BRV的综合分析显示，与低频和高频成分（分别为15.57 %和21.02 %）相比，心脏类器官搏动间隔谱中的频率含量主要非常低（63.42 %）。因此，使用开源的PhysioMEA平台对心脏类器官进行1D和2D电生理分析和BRV评估，显示出不同生理生物标志物在1D上高度相似，而在2D上不相似。

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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 : 2025-12-01 Epub 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

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 : 2025-12-01 Epub 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