Journal of molecular and cellular cardiology最新文献_第4页

Interplay between variability in intrinsic cellular properties and heart failure-associated remodeling in a simulated population with human heart failure 在模拟人类心力衰竭人群中，内在细胞特性变异性与心力衰竭相关重构之间的相互作用

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-18 DOI: 10.1016/j.yjmcc.2025.11.008

Jacob A. Miller , Nicolae Moise , Mario J. Mendez , Seth H. Weinberg

Heart failure (HF) is the presentation of mechanical pump dysfunction, with HF patients facing increased risk of sudden cardiac death predominantly driven by ventricular arrhythmias. At the cellular level, HF is associated with remodeling of ionic currents and fluxes, as well as chronic activation of

β

-adrenergic signaling pathways, ultimately resulting in pathological changes in action potential and intracellular calcium transient characteristics. However, it is challenging to understand the mechanistic underpinnings of HF and associated arrhythmias across diverse populations, due to both inter-individual variability and variability in disease-associated remodeling. In this study, we perform numerical simulations of a model of human ventricular myocytes, utilizing a novel population approach to distinctly represent the variability in both intrinsic cellular properties and properties of HF-associated ionic and

β

-adrenergic signaling remodeling, to predict key outcomes of arrhythmia susceptibility and the presentation of the HF phenotype. We highlight the cellular properties and remodeling leading to both arrhythmia and the HF phenotype, noting key similarities and differences. Critically, we find that the relationship between intrinsic cellular properties and outcome (i.e., arrhythmia susceptibility or the HF phenotype) can be different than the relationship between remodeling severity and outcome, with the expression levels and remodeling severity of inwardly rectifying potassium current (

I_{K 1}

) and the sodium–calcium exchanger (

I_{N a C a}

) as notable examples. Finally, we find that upregulation of specific

β

-adrenergic signaling molecules are predicted to be protective against arrhythmia. Overall, our study presents a novel approach to investigate inter-individual and disease variability and identifies how the interplay between the intrinsic variability in electrophysiology and heart failure-associated remodeling influences arrhythmias in the setting of human heart failure.

心衰（HF）是机械泵功能障碍的表现，心衰患者主要由室性心律失常导致心源性猝死的风险增加。在细胞水平上，HF与离子电流和通量的重塑以及β-肾上腺素能信号通路的慢性激活有关，最终导致动作电位和细胞内钙瞬态特性的病理改变。然而，由于个体间变异性和疾病相关重构的变异性，理解不同人群中HF和相关心律失常的机制基础是具有挑战性的。在这项研究中，我们对人类心室肌细胞模型进行了数值模拟，利用一种新的群体方法来清楚地代表内在细胞特性和HF相关离子和β-肾上腺素能信号重塑特性的可变性，以预测心律失常易感性的关键结果和HF表型的呈现。我们强调导致心律失常和HF表型的细胞特性和重塑，注意到关键的相似性和差异性。重要的是，我们发现内在细胞特性与预后（即心律失常易感性或HF表型）之间的关系可能不同于重构严重程度与预后之间的关系，其中内整流钾电流（IK1）和钠钙交换器（INaCa）的表达水平和重构严重程度是值得注意的例子。最后，我们发现特异性β-肾上腺素能信号分子的上调被预测对心律失常有保护作用。总的来说，我们的研究提出了一种新的方法来研究个体间和疾病变异性，并确定电生理的内在变异性和心力衰竭相关重构之间的相互作用如何影响人类心力衰竭情况下的心律失常。

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引用次数: 0

Spatiotemporal determinants of stretch-activated channel-induced re-entry in ventricular tissue: An in-silico study 拉伸激活通道诱导心室组织再入的时空决定因素：一项计算机研究。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-17 DOI: 10.1016/j.yjmcc.2025.11.007

Melania Buonocunto , Tammo Delhaas , Aurore Lyon , Jordi Heijman , Joost Lumens

Stretch-activated ion channels (SACs) mediate mechano-electric feedback in cardiomyocytes by coupling mechanical and electrical activity. While SACs activation can induce pro-arrhythmic effects at the cellular level, its impact on tissue-level arrhythmias remains poorly understood. Particularly unclear are the specific stretch characteristics that promote arrhythmogenesis, a knowledge gap largely due to limited experimental control over these parameters.

We investigated how SACs activation affects excitation-wave propagation in simulated ventricular tissue and identified parameters promoting arrhythmias, with relevance to commotio cordis, in which a chest impact can trigger ventricular arrhythmias and sudden cardiac death. Our approach employed a validated human ventricular action potential model incorporating three types of SACs (non-selective, potassium-selective, and calcium-selective) applied to a two-dimensional tissue framework. Through systematic multiparameter analysis, we examined the effects of stretch stimulus parameters (amplitude, duration, timing), spatial characteristics (area, location, gradient), and tissue properties (size, conduction velocity).

Our simulations revealed that re-entry arises from interactions between stretch-induced depolarization waves and repolarization tails of preceding excitation waves. Acute supra-threshold stretch (i.e., stretch able to trigger an action potential) initiated re-entries with increased likelihood when path lengths were longer and when stretched regions were closer to non-conducting borders oriented perpendicular to the line of block. Furthermore, stretch amplitude gradients attenuated pro-arrhythmic effects, while sustained sub-threshold stretch either reduced conduction velocity or caused conduction block. This in silico analysis demonstrates that tissue-level proarrhythmic effects of stretch depend on complex interactions between stretch stimulus characteristics, spatial parameters, and tissue properties.

拉伸激活离子通道（SACs）通过耦合机械和电活动介导心肌细胞的机电反馈。虽然SACs激活可以在细胞水平诱导促心律失常作用，但其对组织水平心律失常的影响尚不清楚。尤其不清楚的是促进心律失常发生的特定拉伸特征，这一知识差距主要是由于对这些参数的实验控制有限。我们研究了SACs激活如何影响模拟心室组织中的兴奋波传播，并确定了促进心律失常的参数，与心绞痛相关，其中胸部撞击可引发室性心律失常和心源性猝死。我们的方法采用了一个经过验证的人类心室动作电位模型，该模型将三种类型的SACs（非选择性、钾选择性和钙选择性）应用于二维组织框架。通过系统的多参数分析，我们研究了拉伸刺激参数（振幅、持续时间、时间）、空间特征（面积、位置、梯度）和组织特性（大小、传导速度）的影响。我们的模拟表明，再入是由拉伸诱导的退极化波和前激励波的复极化尾之间的相互作用引起的。急性超阈拉伸（即能够触发动作电位的拉伸）在路径长度较长且拉伸区域更接近于垂直于块线的非导电边界时，会增加重新进入的可能性。此外，拉伸幅度梯度减弱了促心律失常效应，而持续的亚阈值拉伸要么降低了传导速度，要么导致传导阻滞。这一计算机分析表明，拉伸的组织水平致心律失常效应取决于拉伸刺激特征、空间参数和组织特性之间复杂的相互作用。

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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 : 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

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 : 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

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 : 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。

{"title":"Soluble epoxide hydrolase deficiency rescues heart failure with preserved ejection fraction by targeting cytochrome P450 2E1","authors":"Min Zhang , Chen Chen , Xinxing Liu , Zhou Zhou , Gen Li , Xiangrui Jiang , Jingshan Shen , Hualiang Jiang , Zheng Wen , Yan Liu , Dao Wen Wang","doi":"10.1016/j.yjmcc.2025.11.005","DOIUrl":"10.1016/j.yjmcc.2025.11.005","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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)<sup>191</sup>, 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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"210 ","pages":"Pages 98-108"},"PeriodicalIF":4.7,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 : 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

Novel angiotensin receptor target as therapy for the diabetic heart: the AT2R 新的血管紧张素受体靶点治疗糖尿病心脏：AT2R。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-11 DOI: 10.1016/j.yjmcc.2025.11.003

Mandy Li, Yan Wang, Robert E. Widdop

Diabetic-related heart complications, exemplified by heart failure, represents a growing global health burden, characterised by deterioration of cardiac function, disturbances in cardiac structure such as left ventricular geometry and tissue composition. The underlying molecular mechanisms of diabetic heart failure are multifaceted, and both inflammation and oxidative stress are identified as key drivers in disease progression. Current treatments primarily focus on glycaemic control to prevent heart failure in diabetic patients, but their direct effects on the myocardium are not always clear. Upregulation of the renin-angiotensin system in the diabetic heart presents itself as a compelling therapeutic opportunity, particularly through the counter-regulatory angiotensin II type 2 receptor (AT₂R) axis. AT₂R activation confers cardioprotection in experimental diabetes and heart failure by attenuating pathological cardiac remodelling, including fibrosis and hypertrophy. These effects are facilitated by reductions in oxidative stress and endothelial dysfunction, enhanced nitric oxide signalling and suppression of NF-κB signalling and subsequent inflammation. This review describes the progress made to date, profiling the preclinical benefits of AT₂R activation, using a suite of current and new-generation AT₂R agonists in the heart, and provides evidence for the potential therapeutic use of AT₂R agonists as a novel anti-fibrotic strategy, alone or in combination with standard therapy, for diabetic heart failure.

以心力衰竭为代表的与糖尿病有关的心脏并发症是日益严重的全球健康负担，其特点是心功能恶化、左心室几何形状和组织组成等心脏结构紊乱。糖尿病性心力衰竭的潜在分子机制是多方面的，炎症和氧化应激都被认为是疾病进展的关键驱动因素。目前的治疗主要集中在血糖控制以预防糖尿病患者的心力衰竭，但其对心肌的直接影响并不总是明确的。糖尿病心脏肾素-血管紧张素系统的上调是一个令人信服的治疗机会，特别是通过抗调节血管紧张素II型2受体（AT2R）轴。AT2R激活通过减轻病理性心脏重构（包括纤维化和肥厚），为实验性糖尿病和心力衰竭患者提供心脏保护。氧化应激和内皮功能障碍的减少、一氧化氮信号的增强、NF-κB信号和随后的炎症的抑制促进了这些作用。这篇综述描述了迄今为止取得的进展，分析了AT2R激活的临床前益处，在心脏中使用了一套当前和新一代的AT2R激动剂，并为AT2R激动剂作为一种新的抗纤维化策略的潜在治疗用途提供了证据，单独或与标准治疗联合，用于糖尿病性心力衰竭。

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引用次数: 0

The RNA-binding protein Quaking is essential for cardiac homeostasis and function by regulating Morf4l2 splicing rna结合蛋白震动通过调节Morf4l2剪接对心脏稳态和功能至关重要。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-08 DOI: 10.1016/j.yjmcc.2025.11.002

Sunaina Kumari , Shashi , Sandhya Singh , Abinash Swain , Shakti Prakash , Pragya Chitkara , Rakesh Kumar Sharma , Pratyush Agarwal , Samprikta Kundu , Aakash Gaur , Renu Kumari , Abhipsa Sinha , Shambhabi Chatterjee , Pankaj Prasun , Oliver Hummel , Bhaskar Pant , Kinshuk Raj Srivastava , Norbert Hübner , Dipak Datta , Kalyan Mitra , Shashi Kumar Gupta

Background

Lower levels of Qki were reported in human and mouse-failing hearts, implicating its involvement in cardiac diseases. However, the molecular and functional effects of its downregulation in adult myocardium remain largely unknown.

Objective

We aim to uncover the effects of Qki knockdown in adult hearts.

Methods & results

Here we show that AAV9-mediated knockdown of Qki by shRNAs in the hearts of adult BALB/c mice led to cardiac malfunction, atrophy, apoptosis, heart failure, and death within two weeks. Global transcriptomic analysis of Qki knockdown hearts revealed significant dysregulation of 996 alternative splicing events upon Qki knockdown. Mechanistically, we discovered that loss of Qki promotes the exclusion of the third exon of Morf4l2, leading to higher expression of exon three excluded variant (Morf4l2Δex3). Like rodents, the RNA-seq dataset from 108 human hearts revealed a lower splice junction count of MORF4L2 exon three in hearts with low levels of QKI compared to subjects with higher QKI levels. Specific knockdown of Morf4l2Δex3 rescues Qki knockdown-induced cardiac cachexia and improves cardiac function. Moreover, Morf4l2Δex3 was increased in the colon cancer-induced cardiac cachexia mouse model, and its inhibition prevented cardiac cachexia and improved cardiac function. Mechanistically, exon three of Morf4l2 lies in the 5’UTR, and its exclusion leads to higher expression of MORF4L2 upon Qki knockdown due to the lack of a G2-quadruplex. Importantly, MORF4L2 protein sequence and localization were not affected by alternative splicing as exon three lies in the 5’UTR. We found that MORF4L2 is a chromatin-bound protein and regulates H3K27ac.

Conclusion

Qki knockdown in the adult heart leads to cardiac cachexia due to the alteration of Morf4l2 splicing. Inhibition of Morf4l2Δex3 inhibits cancer-induced cardiac cachexia, demonstrating it as a potential therapeutic target.

背景：据报道，在人类和小鼠衰竭的心脏中，Qki水平较低，这意味着它与心脏病有关。然而，其下调在成人心肌中的分子和功能作用在很大程度上仍然未知。目的：揭示Qki基因敲低在成人心脏中的作用。方法与结果：在成年BALB/c小鼠的心脏中，我们发现aav9介导的shrna敲低Qki可导致心脏功能障碍、萎缩、细胞凋亡、心力衰竭和两周内死亡。Qki基因敲低心脏的全球转录组学分析显示，Qki基因敲低后，996个备选剪接事件显著失调。从机制上讲，我们发现Qki的缺失促进Morf4l2的第三外显子被排除，导致第三外显子被排除的变体表达增加（Morf4l2Δex3）。与啮齿类动物一样，来自108个人类心脏的RNA-seq数据集显示，与QKI水平较高的受试者相比，QKI水平较低的心脏中MORF4L2外显子3的剪接连接计数较低。特异性敲低Morf4l2Δex3可缓解Qki敲低引起的心脏恶病质，改善心功能。此外，Morf4l2Δex3在结肠癌诱导的心脏恶病质小鼠模型中表达增加，其抑制作用可预防心脏恶病质，改善心功能。从机制上讲，Morf4l2的外显子3位于5'UTR，由于缺乏g2 -四重体，它的排除导致Qki敲低时Morf4l2的表达增加。重要的是，MORF4L2蛋白的序列和定位不受选择性剪接的影响，因为外显子3位于5'UTR中。我们发现MORF4L2是一种染色质结合蛋白并调节H3K27ac。结论：成人心脏Qki基因敲低可通过Morf4l2剪接改变导致心脏恶病质的发生。抑制Morf4l2Δex3抑制癌症诱导的心脏恶病质，证明它是一个潜在的治疗靶点。

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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 : 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

The influence of lactation on postpartum murine heart growth 哺乳对产后小鼠心脏生长的影响。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-01 DOI: 10.1016/j.yjmcc.2025.10.012

Molly S. Kaissar , Elnaz Ghajar-Rahimi , Adalyn Meeks , Arden Shen , Yusheng Wu , Craig J. Goergen , Kyoko Yoshida

The cardiovascular system adapts to meet rising physiological demands throughout pregnancy. Notably, the left ventricle grows to support this increased workload, which is thought to reverse after delivery. Yet, whether the heart returns to its pre-pregnant size, shape, and function postpartum is unclear. This postpartum cardiac recovery has been historically studied in rodents. However, despite previous research showing that postpartum-specific conditions like lactation affect hemodynamics and heart weight, the relationship between these hemodynamic changes and cardiac growth remains unclear. In this study, we investigate the impact of lactation on postpartum cardiac recovery. We monitored changes in left ventricular mass, volume, and function throughout pregnancy and postpartum in mice using 4D cardiac ultrasound in animals allowed to nurse their pups for 21 days postpartum and in those whose pups were removed immediately after delivery. We analyzed the relationship between the observed hemodynamics and heart growth in these mice using an existing multiscale computational model of heart growth. Here, we observe that pregnancy-induced cardiac hypertrophy reverses by one week postpartum in non-lactating mice but continues increasing after delivery in lactating mice. Our computational analysis suggests that hemodynamic and biological factors have distinct but complementary roles in driving postpartum growth. Further, our animal-specific simulations indicate that individual hemodynamic changes contribute to the observed variability in experimental heart growth, particularly throughout lactation. Overall, this study provides a detailed timeline of cardiac hypertrophy during and after pregnancy, emphasizes the significance of lactation status on postpartum recovery, and highlights the importance of hemodynamics to this phenomenon.

在怀孕期间，心血管系统会适应不断上升的生理需求。值得注意的是，左心室的生长以支持这种增加的工作量，这被认为在分娩后会逆转。然而，心脏是否能恢复到怀孕前的大小、形状和产后功能还不清楚。这种产后心脏恢复已经在啮齿类动物中进行了历史研究。然而，尽管先前的研究表明，产后特殊情况（如哺乳）会影响血流动力学和心脏重量，但这些血流动力学变化与心脏生长之间的关系尚不清楚。在本研究中，我们探讨了哺乳对产后心脏恢复的影响。我们使用4D心脏超声监测小鼠妊娠期间和产后左心室质量、体积和功能的变化，这些小鼠在产后21 天内被允许喂养它们的幼崽，以及在分娩后立即取出幼崽的小鼠。我们使用现有的心脏生长多尺度计算模型分析了这些小鼠观察到的血流动力学与心脏生长之间的关系。在这里，我们观察到妊娠引起的心脏肥厚在非哺乳期小鼠产后一周逆转，但在哺乳期小鼠分娩后继续增加。我们的计算分析表明，血液动力学和生物学因素在推动产后生长方面具有不同但互补的作用。此外，我们的动物特异性模拟表明，个体血流动力学变化有助于观察到实验心脏生长的变异性，特别是在哺乳期。总的来说，本研究提供了怀孕期间和怀孕后心脏肥厚的详细时间线，强调了哺乳状态对产后恢复的重要性，并强调了血流动力学对这一现象的重要性。

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引用次数: 0