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

Generation and evaluation of a novel PI3K-targeting gene therapy in the failing mouse heart and healthy sheep heart 一种新的pi3k靶向基因治疗衰竭小鼠心脏和健康绵羊心脏的产生和评估

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-07-31 DOI: 10.1016/j.jmccpl.2025.100478

Sebastian Bass-Stringer , Daniel G. Donner , Clive N. May , Aya Matsumoto , Emma I. Masterman , Aascha A. D'Elia , Yi Ching Chen , Helen Kiriazis , Jieting Luo , Roger Chooi , Clara Liu Chung Ming , Paul Gregorevic , Colleen J. Thomas , Bianca C. Bernardo , Kate L. Weeks , Julie R. McMullen

Heart failure (HF) remains a clinical challenge with cardiac dysfunction typically progressing even with treatment, and heart transplants only available to small numbers. We previously identified phosphoinositide 3-kinase (PI3K, p110α) as a master regulator of exercise-induced cardioprotection, and showed that gene therapy, incorporating a constitutively active form of PI3K (caPI3K) improved function of the failing mouse heart. However, this approach was not cardiac-specific and the gene therapy was challenging to manufacture. The aim of this study was to develop new PI3K-based gene therapies with more optimal properties for clinical translation. We generated and assessed adeno-associated viruses (AAV6) encoding various PI3K constructs, with different enhancers, promoters and transgene components in healthy adult male mice. The most promising AAV construct based on AAV expression, cardiac-specificity, and ease of manufacture contained a cardiac troponin T (cTnT) promoter together with a small region of the regulatory subunit of PI3K (iSH2), and an intron from the β-globin gene which enhances transcription (IVS2). This AAV (1 × 10¹², 2 × 10¹² vg) was administered to mice with myocardial ischemia/reperfusion injury (I/R: 1 h ischemia with reperfusion; AAV delivered 24 h post-I/R). Direct cardiac injections of PI3K-based AAVs were also performed in healthy adult female sheep. I/R mouse hearts treated with the AAV6-cTnT-IVS2-iSH2 displayed increased phosphorylation of Akt, but no improvement in cardiac function or structure was observed. AAV6-cTnT-IVS2-iSH2 successfully transduced healthy sheep hearts which increased endogenous PI3K catalytic activity. Further testing/optimization of the AAV (time of delivery and/or duration) will be required to assess the therapeutic potential of this approach.

心力衰竭（HF）仍然是一个临床挑战，即使治疗，心脏功能障碍通常也会恶化，心脏移植只适用于少数人。我们之前确定了磷酸肌肽3-激酶（PI3K, p110α）是运动诱导的心脏保护的主要调节因子，并表明基因治疗，包括组成活性形式的PI3K （caPI3K）改善了衰竭小鼠的心脏功能。然而，这种方法不是针对心脏的，而且这种基因疗法的制造具有挑战性。本研究的目的是开发新的基于pi3的基因疗法，具有更理想的临床转化特性。我们在健康成年雄性小鼠中生成并评估了编码多种PI3K构建体、具有不同增强子、启动子和转基因成分的腺相关病毒（AAV6）。基于AAV表达、心脏特异性和易于制造的最有希望的AAV构建物包含一个心脏肌钙蛋白T （cTnT）启动子、PI3K调控亚基的一个小区域（iSH2）和一个来自β-珠蛋白基因的内含子，该内含子可促进转录（IVS2）。将AAV （1 × 1012,2 × 1012vg）给予心肌缺血/再灌注损伤小鼠(I/R：缺血再灌注1 h；AAV在i /R后24小时交付)。在健康成年母羊中也进行了基于pi3的aav直接心脏注射。AAV6-cTnT-IVS2-iSH2处理的I/R小鼠心脏显示Akt磷酸化增加，但未观察到心脏功能或结构的改善。AAV6-cTnT-IVS2-iSH2成功转导了健康绵羊心脏，增加了内源性PI3K的催化活性。需要进一步测试/优化AAV（给药时间和/或持续时间）来评估该方法的治疗潜力。

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引用次数: 0

Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure 人心力衰竭时线粒体、脂滴及肌浆网附着的超微结构分析

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-06-10 DOI: 10.1016/j.jmccpl.2025.100461

Nadina R. Latchman , Tyler L. Stevens , Kenneth C. Bedi , Benjamin L. Prosser , Kenneth B. Margulies , John W. Elrod

Background

Cardiomyocyte structural remodeling is reported as a causal contributor to heart failure (HF) development and progression. Growing evidence highlights the role of organelle apposition in cardiomyocyte function and homeostasis. Disruptions in organelle crosstalk, such as that between the sarcoplasmic reticulum (SR) and mitochondria, dysregulate numerous cellular processes that include calcium handling and cellular bioenergetics, two processes that are disrupted and implicated in cardiac pathophysiology. While the physical distance between organelles is thought to be essential for homeostatic cardiomyocyte function, whether the interactions and coupling of organelles are altered in human heart failure remains unclear.

Methods

Here, we utilized transmission electron microscopy to characterize the role of organelle apposition in cardiomyocytes from patients with various etiologies of HF. Subsequently, we employed molecular approaches to examine expression changes of proposed organelle tethers.

Results

We demonstrate that cardiomyocytes from dilated cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy hearts display smaller, rounded mitochondria as compared to nonfailing controls. Failing cardiomyocytes also exhibited disrupted SR-mitochondria juxtaposition and changes in the expression of various proposed molecular tethers. Further analysis revealed alterations in lipid droplet dynamics including decreased lipid droplet number and less lipid droplets in association with mitochondria in failing cardiomyocytes.

Conclusion

We observed dysregulated organelle dynamics which was conserved across various etiologies of heart failure. Our results suggest that organelle structure and apposition is a possible contributor to human HF progression.

背景心肌细胞结构重塑被认为是心力衰竭（HF）发生和发展的一个原因。越来越多的证据强调了细胞器在心肌细胞功能和稳态中的作用。细胞器串扰的破坏，如肌浆网（SR）和线粒体之间的串扰，会导致许多细胞过程失调，包括钙处理和细胞生物能量学，这两个过程被破坏并与心脏病理生理有关。虽然细胞器之间的物理距离被认为对稳态心肌细胞功能至关重要，但在人类心力衰竭中，细胞器的相互作用和偶联是否发生了改变尚不清楚。方法在此，我们利用透射电子显微镜来表征各种病因的心衰患者心肌细胞中细胞器附着的作用。随后，我们采用分子方法检测细胞器系链的表达变化。结果我们证明，扩张型心肌病、肥厚型心肌病和缺血性心肌病心脏的心肌细胞与非衰竭对照组相比，线粒体更小、更圆。衰竭的心肌细胞也表现出中断的sr -线粒体并置和各种分子链表达的变化。进一步的分析揭示了脂滴动力学的改变，包括脂滴数量的减少和与衰竭心肌细胞线粒体相关的脂滴减少。结论我们观察到细胞器动力学异常在各种心力衰竭病因中都是保守的。我们的研究结果表明，细胞器结构和对立可能是人类HF进展的一个因素。

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引用次数: 0

Combined genome and transcriptome analysis identifies molecular signatures of aortic disease in patients with Marfan syndrome 联合基因组和转录组分析确定马凡氏综合征患者主动脉疾病的分子特征

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-06-19 DOI: 10.1016/j.jmccpl.2025.100467

Katherine B. Stanley , Alexa V. Mederos , Ethan H. Barksdale , Joel S. Corvera , Joshua L. Davis , Fang Fang , Hongyu Gao , Courtney E. Vujakovich , Yunlong Liu , Stephanie M. Ware , Benjamin J. Landis

Introduction

Transcriptional dysregulation in patients with Marfan syndrome (MFS) is complex and not well-defined. There are likely patient-specific and general mechanisms in the aortic pathology. In this study, we combine genome and transcriptome data from patients with MFS to determine the transcriptional impacts of disease-causing variants in FBN1.

Methods

Prospectively enrolled participants provided blood and aortic tissue samples. Smooth muscle cells (SMCs) were cultured directly from the proximal aortic tissues of MFS cases undergoing aortic root replacement and controls during heart transplant. Genome sequencing (GS) analysis was combined with mRNA-sequencing (mRNA-seq) and single-cell gene expression profiling of SMCs. Findings in SMC culture analysis were further investigated in primary frozen aortic tissues.

Results

Automatic annotation of single-cell expression profiles classified 99% of cultured cells as SMCs. All disease-causing FBN1 variants were detected in both GS and SMC mRNA-seq reads. These included missense single nucleotide variants (SNVs), a whole-exon deletion, and a predicted stopgain SNV. Gene and allelic expression abnormalities in FBN1 were identified. Broadly, genes that were dysregulated in MFS were enriched for glycerophospholipid metabolism, immune, potassium channel, and extracellular matrix processes. Single-cell clustering analysis identified subtypes of SMCs. Some genes were differentially expressed in MFS across multiple SMC subtypes (e.g. TRPV2), whereas others were significant within specific SMC states (e.g. TGFB2 in SMCs expressing inflammatory markers).

Conclusions

mRNA-seq analysis of SMCs accurately identified FBN1 variants. General and patient-specific effects on allelic and gene expression were identified. Metabolism of glycerophospholipids may be dysregulated in aortic SMCs in MFS. Identifying pathogenic features with transcriptome analysis may guide novel diagnostic and therapeutic strategies.

马凡氏综合征（MFS）患者的转录失调是复杂且不明确的。主动脉病变可能有患者特异性和一般机制。在这项研究中，我们结合来自MFS患者的基因组和转录组数据来确定FBN1致病变异的转录影响。方法前瞻性招募的参与者提供血液和主动脉组织样本。平滑肌细胞（SMCs）是直接从心脏移植过程中行主动脉根置换术的MFS患者和对照组的主动脉近端组织中培养的。将基因组测序（GS）、mrna测序（mRNA-seq）和SMCs单细胞基因表达谱相结合进行分析。在原发冷冻主动脉组织中进一步研究SMC培养分析结果。结果单细胞表达谱自动注释将99%的培养细胞分类为SMCs。在GS和SMC的mRNA-seq读数中均检测到所有致病的FBN1变异。其中包括错义单核苷酸变异（SNV）、全外显子缺失和预测的停止增益SNV。发现FBN1基因和等位基因表达异常。总的来说，MFS中失调的基因在甘油磷脂代谢、免疫、钾通道和细胞外基质过程中富集。单细胞聚类分析确定了SMCs亚型。在MFS中，一些基因在多个SMC亚型（如TRPV2）中有差异表达，而另一些基因在特定SMC状态下有显著性表达（如表达炎症标志物的SMC中的TGFB2）。结论smrna -seq分析能准确鉴定出FBN1变异。确定了对等位基因和基因表达的一般和患者特异性影响。MFS患者主动脉SMCs中甘油磷脂代谢可能失调。通过转录组分析鉴定病原特征可以指导新的诊断和治疗策略。

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引用次数: 0

Cocaine and the heart – bad news for risk/reward 可卡因和心脏——风险/回报的坏消息

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-07-24 DOI: 10.1016/j.jmccpl.2025.100477

Jules C. Hancox, Andrew F. James

引用次数: 0

Bioinformatics tools for drug repurposing: a tutorial using heart failure as a case study 药物再利用的生物信息学工具：以心力衰竭为案例研究的教程

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-06-16 DOI: 10.1016/j.jmccpl.2025.100460

Ivo Fonseca , Fábio Trindade , Mário Santos , Adelino Leite-Moreira , Daniel Moreira-Gonçalves , Rui Vitorino , Rita Ferreira , Rita Nogueira-Ferreira

Purpose

Drug repurposing is a crucial strategy for researchers worldwide to accelerate drug development and mitigate associated risks and costs. Heart failure (HF) is a major global health problem with high prevalence and mortality rates. There are significant sex differences in HF, including in the risk factors and phenotype, which demand a sex-personalized drug treatment. A convenient approach in that direction is the reuse of drugs already approved for other conditions that are known to interact in sex-biased dysregulated pathways in HF. Numerous bioinformatics tools can help identify those candidates. This tutorial explores the utility of specific bioinformatics tools in identifying drugs to treat HF as a case study.

Methods

Herein, we explain how NeDRex helps identify genes associated with disease and drug repurposing and how functional enrichment analysis can be performed with ShinyGO. We also explain how to predict targets of small bioactive molecules with SwissTargetPrediction and how to retrieve known and predicted interactions between chemicals and proteins with STITCH.

Results

The tutorial demonstrates the use of these tools in searching for new HF treatments.

Conclusion

This tutorial is designed to ease entry into the utilization of the mentioned bioinformatics tools. This approach can also set a precedent for applying such tools to other diseases. The results presented in this tutorial are illustrative and do not constitute definitive evidence. They are intended for demonstration purposes only.

药物再利用是全球研究人员加速药物开发和降低相关风险和成本的关键策略。心力衰竭是一个主要的全球健康问题，发病率和死亡率都很高。心衰存在显著的性别差异，包括危险因素和表型，这需要性别个性化的药物治疗。在这个方向上，一个方便的方法是重复使用已经被批准用于其他疾病的药物，这些药物已知会在心衰的性别偏倚失调途径中相互作用。许多生物信息学工具可以帮助识别这些候选者。本教程以案例研究为例，探讨了特定生物信息学工具在识别治疗心衰药物方面的应用。方法在本文中，我们解释了NeDRex如何帮助识别与疾病和药物再利用相关的基因，以及如何使用ShinyGO进行功能富集分析。我们还解释了如何使用SwissTargetPrediction预测小生物活性分子的靶标，以及如何使用STITCH检索已知和预测的化学物质与蛋白质之间的相互作用。结果本教程演示了这些工具在寻找新的心衰治疗方法中的应用。本教程的目的是为了方便入门使用上述生物信息学工具。这种方法还可以为将此类工具应用于其他疾病开创先例。本教程中提供的结果是说明性的，并不构成确定的证据。它们仅用于演示目的。

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引用次数: 0

Disruption of ventricular activation by subthreshold delayed afterdepolarizations in RyR2-R420Q catecholaminergic polymorphic ventricular tachycardia RyR2-R420Q儿茶酚胺能多形性室性心动过速的阈下延迟后去极化对心室激活的破坏

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-06-11 DOI: 10.1016/j.jmccpl.2025.100466

Ewan D. Fowler , Salimata L. Diakite , Ana M. Gomez , Michael A. Colman

Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) carries increased risk of ventricular arrhythmias due to altered Ca²⁺ regulation associated with mutations in the ryanodine receptor (RyR2). Increased Ca²⁺ leak is believed to result in diastolic Ca²⁺ waves and delayed afterdepolarization (DADs) in cardiac myocytes, but it is uncertain how these cellular events induce ventricular tachycardia in the whole heart. We utilised a transgenic mouse model of human RyR2-R420Q (R420Q) CPVT mutation and a range of electrical and optical mapping technologies to examine the role of DAD-induced conduction abnormalities.

Methods

Heterozygous R420Q and wildtype (WT) control hearts were perfused on a Langendorff apparatus. Electrical activity was monitored using volume conducted ECG electrodes and monophasic action potential (MAP) electrode recordings. Left ventricular activation and membrane potential changes were recorded using an 8 × 8 multielectrode array and optical mapping, respectively.

Results

ECG recordings showed spontaneous ventricular arrhythmias in isolated R420Q hearts. More severe arrhythmias occurred in R420Q hearts following rapid electrical pacing combined with isoproterenol stimulation. Ventricular activation time was not different between genotypes, regardless of stimulation frequency or isoproterenol. Phase differences in local activation times were greater in R420Q hearts during 10 Hz pacing with isoproterenol, suggesting local conduction slowing. Optical mapping experiments revealed subthreshold DADs occurring in R420Q hearts during diastolic pauses. DADs prolonged the subsequent action potential and were associated with conduction slowing during the second beat after the DAD, but not the first beat. 2D tissue simulations revealed that direct inactivation of I_Na during DADs, or indirectly via cycle length dependent refractory mechanisms could account for local conduction slowing.

Conclusions

Increased activation dispersion could arise from subthreshold DADs in R420Q mouse hearts and may contribute to conduction block. This could increase the propensity for re-entrant arrhythmias in CPVT without directly triggering ectopic beats.

儿茶酚胺能多态性室性心动过速（CPVT）由于与ryanodine受体（RyR2）突变相关的Ca2+调节改变而增加室性心律失常的风险。增加的Ca2+泄漏被认为会导致心肌细胞舒张期Ca2+波和延迟后去极化（DADs），但不确定这些细胞事件如何诱导整个心脏的室性心动过速。我们利用人类RyR2-R420Q (R420Q) CPVT突变转基因小鼠模型和一系列电学和光学定位技术来研究dad诱导的传导异常的作用。方法在Langendorff仪上灌注异合子R420Q和野生型（WT）对照心脏。电活动监测采用体积传导ECG电极和单相动作电位（MAP）电极记录。采用8 × 8多电极阵列和光学成像分别记录左心室激活和膜电位变化。结果在离体R420Q心脏中出现自发性室性心律失常。快速电起搏联合异丙肾上腺素刺激后，R420Q心脏发生更严重的心律失常。与刺激频率或异丙肾上腺素无关，不同基因型的心室激活时间无差异。在10hz异丙肾上腺素起搏时，R420Q心脏局部激活时间的相位差更大，表明局部传导减慢。光学测绘实验显示，R420Q心脏在舒张期暂停时发生阈下DADs。DADs延长了随后的动作电位，并与DAD后第二次心跳的传导减慢有关，但与第一次心跳无关。二维组织模拟显示，在DADs期间，INa的直接失活，或间接通过周期长度依赖的难熔机制，可以解释局部传导减慢。结论R420Q小鼠心脏阈下DADs激活弥散度增加，可能导致传导阻滞。这可能会增加CPVT再入性心律失常的倾向，而不会直接引发异位搏。

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引用次数: 0

Semaphorin 3F is elevated in serum of heart failure patients and inhibits cardiac angiogenesis via the VEGF/Akt/eNOS pathway Semaphorin 3F在心力衰竭患者的血清中升高，并通过VEGF/Akt/eNOS途径抑制心脏血管生成

Journal of molecular and cellular cardiology plus

Pub Date : 2025-09-01 Epub Date: 2025-06-25 DOI: 10.1016/j.jmccpl.2025.100470

Diana Petrova , Miki Weberbauer , Stephanie Reichert , Stephanie Scheid , Jennifer Esser , Katrin Fink , Daniel Duerschmied , Martin Moser , Thomas Helbing

Left ventricular (LV) remodeling in heart failure (HF) is associated with vascular rarefaction and impaired angiogenesis. The inhibition of vascular endothelial growth factor (VEGF)-mediated angiogenesis is a key feature in the pathophysiology of HF. Semaphorin (Sema) 3F is a known inhibitor of VEGF signaling, but its role in HF remains to be elucidated.

Serum Sema3F levels were measured in HF patients (n = 70) by ELISA and were compared to those in patients with coronary artery disease (CAD, n = 26). Sema3F levels were significantly increased in HF patients. Sema3F RNA and protein expression were upregulated by hypoxia in cardiac endothelial cells (HCECs) as demonstrated by quantitative RT-PCR and Western blotting (WB). In Matrigel® sprouting assays, endothelial cell sprouting and branching were decreased in response to HF patient serum, suggesting that HF serum contains anti-angiogenic factors. Recombinant human Sema3F attenuated VEGF-mediated angiogenesis in Matrigel® sprouting, spheroid sprouting and aortic ring assays. Vice versa, siRNA-based Sema3F knockdown promoted angiogenesis. In zebrafish, morpholino-based Sema3F knockdown led to increased mortality and induced a vascular phenotype. Mechanistically, Sema3F inhibited VEGF-induced Akt and eNOS phosphorylation in endothelial cells, and Sema3F knockdown increased phosphorylation of Akt and eNOS.

Sema3F is elevated in serum of HF patients and has anti-angiogenic properties in cardiac angiogenesis through inhibition of the VEGF/Akt/eNOS pathway. Thus, targeting Sema3F could present a therapeutic approach to advanced HF in the future.

心力衰竭（HF）左心室（LV）重构与血管稀疏和血管生成受损有关。抑制血管内皮生长因子（VEGF）介导的血管生成是HF病理生理的一个关键特征。信号素（Sema） 3F是一种已知的VEGF信号抑制剂，但其在HF中的作用仍有待阐明。用ELISA法测定了HF患者（n = 70）的血清Sema3F水平，并与冠心病患者（n = 26）进行了比较。心衰患者的Sema3F水平显著升高。定量RT-PCR和Western blotting （WB）结果显示，缺氧导致心脏内皮细胞（HCECs）中Sema3F RNA和蛋白表达上调。在Matrigel®发芽试验中，内皮细胞发芽和分支减少，这表明HF患者血清含有抗血管生成因子。重组人Sema3F在Matrigel®发芽、球形发芽和主动脉环试验中减弱vegf介导的血管生成。反之亦然，基于sirna的Sema3F敲低促进血管生成。在斑马鱼中，基于morpholino的Sema3F敲低导致死亡率增加并诱导血管表型。在机制上，Sema3F抑制vegf诱导的内皮细胞中Akt和eNOS的磷酸化，Sema3F敲低增加Akt和eNOS的磷酸化。Sema3F在HF患者血清中升高，并通过抑制VEGF/Akt/eNOS通路在心脏血管生成中具有抗血管生成特性。因此，靶向Sema3F可能是未来晚期心衰的一种治疗方法。

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引用次数: 0

Differential regulation during development, aging, and disease implies heart cell specific functions of the Mediator Complex 在发育、衰老和疾病过程中的差异调节暗示了中介复合物的心脏细胞特异性功能

Journal of molecular and cellular cardiology plus

Pub Date : 2025-06-01 Epub Date: 2025-05-22 DOI: 10.1016/j.jmccpl.2025.100456

Dominic W. Kolonay , Chad E. Grueter , Kedryn K. Baskin

Transcription directs the heart's development and adaptation to stress signals, and transcriptional dysregulation contributes to developmental disorders, pathological remodeling and heart failure (HF). Stereotypic changes at the mRNA level in the failing heart can be powerful diagnostics, as dysregulation can precede pathological outcomes such as decreased ejection fraction and increased heart size. The Mediator Complex is a general regulator of transcription in all eukaryotic cells; however, unknown subunit- and tissue-specific functions complicate our understanding of Mediator's influence on the cell. Here, we investigated the subunit-specific responses of Mediator throughout cardiac development, aging, and disease at the single cell- and whole ventricle-resolution using single cell RNA-sequencing, bulk RNA-sequencing, qPCR, and assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) datasets from humans and mice. In the developing heart, we discovered that key stages of growth such as ventricle formation were marked with elevated Mediator component expression, which declined during postnatal maturation, but increased again in the aging heart. Heart failure, a heterogenous disease, presented with a global increase in Mediator expression in human and mouse cardiomyocytes. This increased expression was mirrored by increased chromatin accessibility at the promoters of Mediator genes. Collectively, this study reveals the dynamic expression of Mediator subunits throughout the stages of the cardiomyocyte lifecycle and uncovers potential mechanisms by which Mediator is modulated in response to various pathological stimuli.

转录指导心脏的发育和对应激信号的适应，转录失调有助于发育障碍、病理性重塑和心力衰竭（HF）。在衰竭的心脏中，mRNA水平的典型变化可能是强有力的诊断，因为失调可能先于病理结果，如射血分数降低和心脏大小增加。中介复合物是所有真核细胞中转录的一般调节因子；然而，未知的亚基和组织特异性功能使我们对Mediator对细胞影响的理解复杂化。在这里，我们使用单细胞rna测序、大量rna测序、qPCR和使用人类和小鼠的转座酶可及染色质测序（ATAC-seq）数据集，在单细胞和全心室分辨率下研究了Mediator在心脏发育、衰老和疾病过程中的亚基特异性反应。在心脏发育过程中，我们发现，在心室形成等关键生长阶段，中介成分的表达水平升高，在出生后成熟过程中下降，但在心脏衰老过程中再次升高。心力衰竭是一种异质性疾病，在人和小鼠心肌细胞中表现为中介体表达的全球增加。这种增加的表达反映在中介基因启动子染色质可及性的增加上。总的来说，这项研究揭示了在心肌细胞生命周期的各个阶段中介体亚基的动态表达，并揭示了中介体在各种病理刺激下被调节的潜在机制。

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引用次数: 0

Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants 携带肌瘤致病变异的肥厚性心肌病猪模型的围产期死亡

Journal of molecular and cellular cardiology plus

Pub Date : 2025-06-01 Epub Date: 2025-05-21 DOI: 10.1016/j.jmccpl.2025.100457

Tatiana Flisikowska , Björn Petersen , Giulia Mearini , Daniela Huber , Mayuko Kurome , Melanie Stoff , Saskia Schlossarek , Andrea Lucas-Hahn , Eckhard Wolf , Judith Montag , Angelika Schnieke , Lucie Carrier

Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease caused by genetic variants in sarcomeric proteins, particularly in myosin binding protein C3 (MYBPC3) and myosin heavy chain 7 (MYH7). Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life. Although myosin inhibitors are now used to treat obstructive forms of adult HCM, there is still a need for novel therapeutic options and predictive animal models to assess them. Our aim was to model in pigs severe forms of human HCM carrying bi-allelic truncating MYBPC3 mutations or heterozygous missense MYH7 variants. Pigs were generated by CRISPR/Cas9 genome or cytosine-base editing in porcine fibroblasts combined with somatic cell nuclear transfer. Several pregnancies were established but piglets were non-viable. The MYBPC3-edited piglet exhibited a compound heterozygous mutation leading to a markedly low level of mutant MYBPC3 protein and cardiac hypertrophy, reflecting the situation in infants. The MYH7-edited piglets carried the heterozygous p.Arg453Cys variant and exhibited ventricular hypertrophy. In conclusion, MYBPC3 and MYH7 cloned piglets developed cardiac hypertrophy and died around birth, indicating that pigs are particularly sensitive to sarcomeric gene mutations.

肥厚性心肌病（HCM）是一种常染色体显性疾病，由肌凝蛋白，特别是肌凝蛋白结合蛋白C3 （MYBPC3）和肌凝蛋白重链7 （MYH7）基因变异引起。鲜为人知的是，新生儿形式的HCM会迅速演变为收缩期心力衰竭，并在出生后一年内死亡。尽管肌球蛋白抑制剂现在被用于治疗阻塞性成人HCM，但仍需要新的治疗选择和预测性动物模型来评估它们。我们的目的是在猪身上模拟携带双等位基因截断MYBPC3突变或杂合错义MYH7变异的严重形式的人类HCM。通过CRISPR/Cas9基因组或胞嘧啶碱基编辑在猪成纤维细胞中结合体细胞核移植产生猪。有几只小猪怀孕，但仔猪不能存活。经过MYBPC3编辑的仔猪表现出一种复合杂合突变，导致MYBPC3突变蛋白水平显著降低和心脏肥厚，反映了婴儿的情况。经过myh7编辑的仔猪携带杂合子p.a g453cys变体，并表现出心室肥厚。综上所述，MYBPC3和MYH7克隆仔猪出现心肌肥厚并在出生前后死亡，表明猪对肉瘤基因突变特别敏感。

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引用次数: 0

Is boosting OXPHOS/FAO gene pathways the final end-mechanism of SGLT2i protection? 促进OXPHOS/FAO基因通路是SGLT2i保护的最终机制吗？

Journal of molecular and cellular cardiology plus

Pub Date : 2025-06-01 Epub Date: 2025-04-03 DOI: 10.1016/j.jmccpl.2025.100297

Xin Hu, Coert J. Zuurbier

引用次数: 0