Journal of molecular and cellular cardiology最新文献

The mineralocorticoid receptor: a new chapter for therapeutic regulation of diabetic cardiomyopathy. 糖皮质激素受体：糖尿病性心肌病治疗调控的新篇章。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-14 DOI: 10.1016/j.yjmcc.2026.01.004

Monica Kanki, Morag J Young

Diabetes mellitus is a global health burden and represents a major cause of cardiovascular disease-related morbidity and mortality. Diabetic cardiomyopathy continues to predispose individuals to overt heart failure despite significant advances in the development of anti-hyperglycaemic medications. Currently, there is a lack of biomarkers for the detection of myocardial injury in the early stages of diabetic cardiomyopathy, which underscores the urgent need to identify early disease processes and develop novel therapeutic strategies. The mineralocorticoid receptor (MR) has proven to be a valuable therapeutic target in heart failure, which may translate to a promising option to reduce the risk of cardiovascular complications in mid-to-late stages of diabetic cardiomyopathy. This narrative review discusses the role of inappropriate MR activation in common pathogenic mechanisms underlying diabetic cardiomyopathy, as well as highlighting the circadian clock as an emerging target in diabetes that has been linked to modulation of MR activation. It will also outline the cardiovascular protection yielded from anti-diabetic agents and MR antagonists (MRA) in preclinical and clinical settings of diabetes. Although our knowledge of the mechanisms of myocardial injury in diabetes is expanding quickly, current therapeutic strategies do not mitigate the high risks of cardiovascular disease in this vulnerable population. Further investment in understanding the consequences of adverse MR signalling and potentially the early introduction of MR blockade in management plans may be critical for combating the burden of cardiomyopathy in the diabetic population.

糖尿病是一个全球性的健康负担，是心血管疾病相关发病率和死亡率的主要原因。尽管抗高血糖药物的发展取得了重大进展，但糖尿病性心肌病仍然使个体易患明显的心力衰竭。目前，缺乏用于检测糖尿病性心肌病早期心肌损伤的生物标志物，这强调了迫切需要识别早期疾病过程并开发新的治疗策略。矿物皮质激素受体（MR）已被证明是心力衰竭的一个有价值的治疗靶点，这可能转化为降低中晚期糖尿病心肌病心血管并发症风险的有希望的选择。这篇叙述性综述讨论了不适当的MR激活在糖尿病性心肌病的常见致病机制中的作用，并强调了生物钟作为糖尿病中与MR激活调节有关的新兴靶点。它还将概述抗糖尿病药物和MR拮抗剂（MRA）在糖尿病临床前和临床环境中的心血管保护作用。尽管我们对糖尿病心肌损伤机制的了解正在迅速扩大，但目前的治疗策略并不能降低这一易感人群患心血管疾病的高风险。进一步投资于了解不良MR信号的后果，并可能在管理计划中尽早引入MR阻断，这对于对抗糖尿病人群心肌病的负担至关重要。

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引用次数: 0

METTL3-dependent N6-methyladenosine modification on LGMN mRNA promotes macrophage ferroptosis and atherosclerosis. mettl3依赖性n6 -甲基腺苷修饰LGMN mRNA促进巨噬细胞铁下垂和动脉粥样硬化。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-06 DOI: 10.1016/j.yjmcc.2026.01.003

Yang He, Kaisheng Jiang, Junhong Sun, Qianhao Zhao, Jiacheng Yue, Wenzhao Wei, Jie Cao, Da Zheng, Hui Yao, Shuquan Zhao, Hu Zhao, Erwen Huang

N6-methyladenosine (m6A) modification plays important roles in various biological processes, yet its function in macrophages and its potential link to ferroptosis in promoting atherosclerosis (AS) remain unclear. In this study, elevated levels of m6A modification and methyltransferase-like 3 (METTL3) expression were observed in AS arteries of mice. The number of METTL3-positive macrophages increased in both mouse and human AS arteries. Systemic inhibition or macrophage-specific knockdown of METTL3 attenuated AS plaque formation in mice. RNA-sequencing revealed that ferroptosis-associated genes were enriched following METTL3 knockdown in bone marrow-derived macrophages (BMDM). Consistent with this, inhibition of ferroptosis also reduced AS plaques. Further analysis showed increased m6A modification and expression of legumain (LGMN) in mouse AS arteries. Elevated LGMN expression was also detected in oxidized low-density lipoprotein (ox-LDL)-treated BMDM and in macrophages within AS lesions. Knockdown of LGMN in BMDM attenuated ox-LDL-induced ferroptosis, lipid deposition, and inflammatory responses. Macrophage-specific knockdown of LGMN in mice reduced plaque formation and ferroptosis in AS arteries. Additionally, macrophage-specific METTL3 knockdown suppressed the upregulation of LGMN expression in AS arteries. The effects of ox-LDL on BMDM were abolished by METTL3 knockdown but rescued by LGMN overexpression. Mechanistically, YTHDF1 bound to m6A-methylated LGMN mRNA and enhanced its translation. Together, The in vivo and in vitro results demonstrate that LGMN acts as a novel mediator of AS by linking METTL3-dependent m6A modification to macrophage ferroptosis.

n6 -甲基腺苷（m6A）修饰在多种生物过程中发挥重要作用，但其在巨噬细胞中的功能及其在促进动脉粥样硬化（AS）中的潜在联系尚不清楚。在本研究中，观察到小鼠AS动脉中m6A修饰和甲基转移酶样3 （METTL3）表达水平升高。小鼠和人AS动脉中mettl3阳性巨噬细胞数量均增加。全身抑制或巨噬细胞特异性敲除METTL3可减轻小鼠AS斑块形成。rna测序显示，在骨髓源性巨噬细胞（BMDM）中，METTL3基因敲低后，凋亡相关基因富集。与此一致的是，抑制铁下垂也减少了AS斑块。进一步分析显示，小鼠AS动脉中m6A修饰和豆科蛋白（LGMN）表达增加。在氧化低密度脂蛋白（ox-LDL）处理的BMDM和AS病变内的巨噬细胞中也检测到LGMN表达升高。BMDM中LGMN的下调减轻了ox- ldl诱导的铁下垂、脂质沉积和炎症反应。巨噬细胞特异性敲除小鼠LGMN可减少AS动脉斑块形成和铁下垂。此外，巨噬细胞特异性METTL3敲低可抑制AS动脉中LGMN表达上调。ox-LDL对BMDM的影响被METTL3敲除而被LGMN过表达所恢复。在机制上，YTHDF1结合m6a甲基化LGMN mRNA并增强其翻译。总之，体内和体外结果表明，LGMN通过将mettl3依赖性m6A修饰与巨噬细胞铁凋亡联系起来，作为as的一种新的介质。

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引用次数: 0

Transcription initiation factor-1A regulates the contraction of vascular smooth muscle and maintains blood pressure 转录起始因子- 1a调节血管平滑肌收缩，维持血压。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-05 DOI: 10.1016/j.yjmcc.2026.01.002

Xiaolin Yue , Yawei Wang , Zhinan Wu , Hanlin Lu , Fan Jiang , Wencheng Zhang , Yan Liu

Hypertension is a complex condition influenced by many factors. RNA polymerase I (pol I)-specific transcription initiation factor-1A (TIF-1A) regulates ribosome biosynthesis by participating in the formation of a competent pre-initiation complex. However, limited information is available regarding the role of TIF-1A in vascular smooth muscle cells (VSMCs) and its impact on blood pressure. This study investigated the biological function of TIF-1A in the modulation of smooth muscle contraction and explored the potential therapeutic targets of hypertension. Vascular smooth muscle-specific Tif-1a-knockout (Tif-1a^SMKO) mice were generated by crossbreeding Tif-1a^flox/flox and SMMHC-CreER^T2 mice. The angiotensin II (Ang II)-infused mice and spontaneously hypertensive rats were used as animal models of hypertension. The primary mouse smooth muscle cell model induced by Ang II was used for in vitro observations. Compared to that of the control, the phenotype of the Tif-1a^SMKO mice exhibited lower blood pressure. The contractile response to vasoconstrictors was also lower in mesenteric artery segments isolated from Tif-1a^SMKO mice. Functional abnormalities in Tif-1a^SMKO mice have been attributed to ribosomal dysfunction, which results in decreased ribosomal biosynthesis. Consistently, the expression of proteins associated with smooth muscle contraction decreased in Tif-1a-deficient smooth muscle cells. Finally, the smooth muscle-specific deletion of Tif-1a attenuated Angiotensin II-induced hypertension and vascular remodeling in mice. Administration of RNA pol I transcription inhibitor BMH-21 ameliorates hypertension in spontaneously hypertensive rats. TIF-1A regulated vascular smooth muscle contraction and maintained blood pressure by modulating ribosomal biosynthesis. Thus, TIF-1A inhibition may represent a new research orientation for the treatment of hypertension.

高血压是一种受多种因素影响的复杂疾病。RNA聚合酶I （pol I）特异性转录起始因子- 1a （TIF-1A）通过参与活性起始前复合物的形成来调节核糖体的生物合成。然而，关于tifi - 1a在血管平滑肌细胞（VSMCs）中的作用及其对血压的影响的信息有限。本研究探讨了tifi - 1a在调节平滑肌收缩中的生物学功能，并探索了高血压的潜在治疗靶点。血管平滑肌特异性tifi -1a敲除（tifi - 1asmko）小鼠是通过与SMMHC-CreERT2小鼠杂交产生的。采用血管紧张素II （angii）灌注小鼠和自发性高血压大鼠作为高血压动物模型。采用Angⅱ诱导小鼠平滑肌细胞原代模型进行体外观察。与对照组相比，tifi - 1asmko小鼠表现出较低的血压。从Tif-1aSMKO小鼠分离的肠系膜动脉段对血管收缩剂的收缩反应也较低。tifi - 1asmko小鼠的功能异常归因于核糖体功能障碍，导致核糖体生物合成减少。与此一致的是，在缺乏tif -1a的平滑肌细胞中，与平滑肌收缩相关的蛋白表达减少。最后，小鼠平滑肌特异性缺失Tif-1a可减轻血管紧张素ii诱导的高血压和血管重构。给药RNA pol I转录抑制剂BMH-21可改善自发性高血压大鼠的高血压。tifi - 1a通过调节核糖体生物合成调节血管平滑肌收缩，维持血压。因此，抑制TIF-1A可能是治疗高血压的一个新的研究方向。

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引用次数: 0

AAV-TNNI3 rescues an experimental murine Tnni3 mutation resulting in thin filament mediated DCM AAV-TNNI3可挽救实验性小鼠Tnni3突变导致的细丝介导的DCM。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-04 DOI: 10.1016/j.yjmcc.2026.01.001

Paul J. Bushway , Wei Feng , Marina Sampaio De Menezes Cruz , Sofie Maisel , Aysen Shathaya , Pranita Rao , Umang Patel , Jinsun Park , Chao Chen , Zhiyuan Tang , Betul Gunes , Eren Gunes , Mao Ye , Yusu Gu , Eric Adler

Cardiac thin filament mutations in TNNI3 are associated with up to 3 % of hypertrophic (HCM) cardiomyopathy cases and contribute to severe restrictive (RCM) and dilated (DCM) cardiomyopathy caseloads. As such, thin filament cardiomyopathy mediated by TNNI3 mutations is an orphan disease with unmet therapeutic need. Gene therapy is one approach to addressing orphan disease but has been restricted to the repletion of protein deficiency. Based on the best available knowledge, TNNI3 gene therapy has never been applied in the context of a functional mutant protein. Described here is the viral gene therapy rescue at a 4-month endpoint of an experimental murine Tnni3 mutation resulting in slow-onset dilated cardiomyopathy (DCM) with cardiac failure at 12–18 months. Mutant mice treated with AAV encoding wild-type (WT) human TNNI3 at 1.0E+14 vg/kG prevented the onset of DCM pathology. This work describes the first adeno-associated virus (AAV) gene therapy replacement of functional mutated Tnni3 protein. The results suggest a broader application of gene therapy for gene replacement.

心肌细丝TNNI3突变与高达3 %的肥厚性（HCM）心肌病病例相关，并导致严重限制性（RCM）和扩张性（DCM）心肌病病例负荷。因此，由TNNI3突变介导的细丝心肌病是一种未满足治疗需求的孤儿病。基因治疗是解决孤儿病的一种方法，但一直局限于蛋白质缺乏的补充。基于现有的最佳知识，TNNI3基因治疗从未在功能性突变蛋白的背景下应用。本文描述了一种实验性小鼠Tnni3突变，在12-18 个月时导致慢发扩张型心肌病（DCM）并发心力衰竭，在4个月的终点进行病毒基因治疗。用编码野生型（WT）人TNNI3的AAV 1.0E+14 vg/kG处理突变小鼠，可防止DCM病理的发生。这项工作描述了第一个腺相关病毒（AAV）基因治疗替代功能突变的Tnni3蛋白。研究结果表明，基因治疗在基因替代方面的应用前景广阔。

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引用次数: 0

Atrial t-tubules adopt a distinct developmental state as Ca2+ handling matures postnatally 心房t小管在出生后Ca2+处理成熟时采用独特的发育状态。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-04 DOI: 10.1016/j.yjmcc.2025.12.012

C.E.R. Smith, C.J. Quinn, J.D. Clarke, Z. Sultan, H. Najem, N.C. Denham, D.C. Hutchings, A.S. Whitley, G.W.P. Madders, J.L. Caldwell, L.K. Toms, D.A. Eisner, C. Pinali, A.W. Trafford, K.M. Dibb

Transverse (t)-tubules ensure a uniform rise in cellular Ca²⁺ facilitating cardiac contraction. They play a key role in the large mammalian atria (including human) and their loss in heart failure is associated with impaired Ca²⁺ release. While t-tubule restoration is therefore an ideal therapeutic target, atrial t-tubule development is not well understood. Here we sought to determine how atrial t-tubules develop and the impact on Ca²⁺ handling. Atrial postnatal development was examined in sheep from newborn through to adulthood. T-tubule development was assessed using confocal microscopy and serial block face Scanning Electron Microscopy. Voltage clamp coupled with Ca²⁺ epifluorescence was used to assess concomitant functional changes to Ca²⁺ handling. Atrial t-tubule density increased until 3 months of age when the t-tubule network was disordered. As development continued t-tubules became more ordered but surprisingly the distance of the cell interior to t-tubule membrane increased due to a lack of additional t-tubules coupled with increased cell width. As t-tubules developed, L-type Ca²⁺ current density (I_Ca-L) and sarcoplasmic reticulum (SR) Ca²⁺ content decreased. Although these changes would be expected to decrease Ca²⁺ transient amplitude, Ca²⁺ buffering was simultaneously reduced which our data suggests maintains Ca²⁺ transient amplitude during neonatal development. By understanding how the Ca²⁺ transient is preserved despite drastic changes in t-tubule density and structure during development, this study may provide insights into adaptive mechanisms in Ca²⁺ cycling that mitigate the impact of reduced t-tubule density.

横(t)小管确保细胞Ca2+均匀上升，促进心脏收缩。它们在大型哺乳动物心房（包括人类）中起着关键作用，心力衰竭时它们的丢失与Ca2+释放受损有关。虽然t小管修复因此是一个理想的治疗靶点，但心房t小管的发育尚不清楚。在这里，我们试图确定心房t小管是如何发展的，以及对Ca2+处理的影响。研究了绵羊从新生儿到成年后的心房发育情况。使用共聚焦显微镜和连续块面扫描电子显微镜评估t小管发育。电压钳耦合Ca2+荧光被用来评估伴随的功能变化，以Ca2+处理。心房t小管密度增加至3 月龄，此时t小管网络紊乱。随着发育的继续，t小管变得更加有序，但令人惊讶的是，由于缺乏额外的t小管，加上细胞宽度的增加，细胞内部到t小管膜的距离减少了。随着t小管的发育，l型Ca2+电流密度（ICa-L）和肌浆网（SR） Ca2+含量降低。虽然这些变化预计会降低Ca2+瞬态振幅，Ca2+缓冲同时减少，我们的数据表明，在新生儿发育期间维持Ca2+瞬态振幅。通过了解在发育过程中t小管密度和结构发生剧烈变化时Ca2+瞬态是如何保存的，本研究可能为Ca2+循环中的适应性机制提供见解，从而减轻t小管密度降低的影响。

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引用次数: 0

Watching the clock: Blood pressure and cardiovascular disease influence circadian machinery in pre-clinical models 观察时钟：血压和心血管疾病影响临床前模型中的昼夜节律机制。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2026-01-02 DOI: 10.1016/j.yjmcc.2025.12.010

Sophia A. Eikenberry, Michelle L. Gumz

Circadian rhythms drive cardiovascular health, and when dysfunctional, disease. Circadian biology rules daily rhythms in physiological mechanisms which allow our bodies to coordinate function with the demands of the external environment. However, the machinery underlying circadian rhythms, termed the “molecular clock”, can become altered by both external and internal factors. For instance, breaking the clock through disrupted light exposure can drive high blood pressure, which is detrimental to cardiovascular health. Importantly, cardiovascular disease itself can disrupt the molecular clock, further exacerbating pathology. The focus of this review is this latter aspect of the bi-directional relationship between circadian machinery and cardiovascular function, investigated in preclinical models. First, we describe the importance of blood pressure regulation and relevant systems. We then describe the existence of circadian rhythms in blood pressure, and briefly, how a broken clock can disrupt these rhythms and lead to disease. The focus of this review will be to outline evidence from pre-clinical and translational studies investigating the direct impact of cardiovascular disease on circadian machinery in the brain, heart, aorta, and kidney. This is with the goal of 1) highlighting the potential for harnessing the molecular clock through circadian interventions in combination with other treatment, and 2) aiding pre-clinical cardiovascular researchers in understanding their results which may be impacted by time of day.

昼夜节律驱动心血管健康，如果功能失调，就会引发疾病。昼夜节律生物学在生理机制中规定了日常节律，使我们的身体能够根据外部环境的需求协调功能。然而，昼夜节律背后的机制，被称为“分子钟”，可以被外部和内部因素改变。例如，通过被干扰的光照打破生物钟会导致高血压，这对心血管健康有害。重要的是，心血管疾病本身可以破坏分子钟，进一步加剧病理。本综述的重点是在临床前模型中研究的昼夜节律机制和心血管功能之间双向关系的后一个方面。首先，我们描述了血压调节和相关系统的重要性。然后，我们描述了血压中昼夜节律的存在，并简要介绍了生物钟如何破坏这些节律并导致疾病。本综述的重点是概述来自临床前和转化研究的证据，这些研究调查了心血管疾病对大脑、心脏、主动脉和肾脏的昼夜机制的直接影响。这样做的目的是：1)强调通过与其他治疗相结合的昼夜节律干预来利用分子钟的潜力；2)帮助临床前心血管研究人员了解他们的结果可能受到一天中时间的影响。

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引用次数: 0

Phenotypes and mechanisms of dysfunctional cardiac T-lymphocytes in dilated cardiomyopathy patients 扩张型心肌病患者心肌t淋巴细胞功能障碍的表型和机制。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-24 DOI: 10.1016/j.yjmcc.2025.12.011

Austin Angelotti , Thiruvelselvan Ponnusamy , Vinay Kumar , Gianna V. Passarelli , Jozef Malysz , Balakrishnan Mahesh , Behzad Soleimani , Elisa A. Bradley , Shyam S. Bansal

Background

Dilated cardiomyopathy (DCM) is characterized by increased infiltration and activation of the innate immune system, including neutrophils, monocytes/macrophages, and dendritic cells. However, the phenotypic profile of cardiac CD3⁺ T-cells and its CD4⁺ and CD8⁺ subsets have not been characterized in DCM patients.

Methods

We studied phenotypic signatures of T-cell subsets by analyzing publicly available single-cell and single-nuclear transcriptomic datasets from control and failing hearts of DCM patients.

Results

Our analysis revealed increased cardiac infiltration of CD3⁺ T-cells in DCM patients with transcriptomic signatures indicating antigenic activation, T-cell exhaustion, diminished oxidative phosphorylation, and elevated TNF/NFκB and profibrotic TGF signaling. Among T-cell subsets, both CD4⁺ and CD8⁺ T-cells were found to be highly proliferative (increased G2M) and activated. Transcription profiling demonstrated four phenotypically different subsets for both CD8⁺ and CD4⁺ T-cells, however, only CD4⁺ T-cell subsets, regulatory T-cells and tissue resident memory (TRM) CD4⁺ T-cells, were significantly increased. Importantly, TRM cells displayed decreased expression of classical egress markers, such as CCR7, SELL, and MAL, and increased pro-inflammatory and pro-fibrotic signaling. We also observed increased estrogen receptor (ER)α expressing (with amplified ERα signaling) cardiac CD4⁺ T-cells which directly correlated with systolic dysfunction and mediated their pro-fibrotic effects in DCM patients.

Conclusion

Here we demonstrate for the first time, an “activated phenotype” with increased pro-inflammatory and profibrotic signaling in cardiac CD3⁺ T-cells and its CD4⁺ helper T-cell subset in DCM hearts. Notably, increased ERα signaling provide novel avenues for targeted immunomodulatory therapies to modify DCM progression.

背景：扩张型心肌病（DCM）的特点是先天免疫系统的浸润和激活增加，包括中性粒细胞、单核/巨噬细胞和树突状细胞。然而，心脏CD3+ t细胞及其CD4+和CD8+亚群的表型特征尚未在DCM患者中得到表征。方法：我们通过分析来自DCM患者对照和衰竭心脏的公开的单细胞和单核转录组数据集来研究t细胞亚群的表型特征。结果：我们的分析显示，DCM患者心脏中CD3+ t细胞浸润增加，转录组特征表明抗原激活、t细胞耗竭、氧化磷酸化减少、TNF/NFκB和促纤维化TGF信号升高。在t细胞亚群中，CD4+和CD8+ t细胞均具有高度增殖（G2M增加）和活化。转录分析显示CD8+和CD4+ t细胞有四个表型不同的亚群，然而，只有CD4+ t细胞亚群，调节性t细胞和组织常驻记忆（TRM） CD4+ t细胞显著增加。重要的是，TRM细胞显示经典的出口标记物，如CCR7、SELL和MAL的表达减少，促炎和促纤维化信号增加。我们还观察到，DCM患者心肌CD4+ t细胞中表达雌激素受体(ER)α的细胞（伴有扩增的ERα信号）增加，与收缩功能障碍显著相关，并介导其促纤维化作用。结论：我们首次证明，在DCM心脏中，心脏CD3+ t细胞及其CD4+辅助性t细胞亚群中存在促炎和促纤维化信号增加的“活化表型”。值得注意的是，ERα信号的增加为靶向免疫调节治疗改变DCM进展提供了新的途径。

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引用次数: 0

Pseudo-acetylation of ACTC1 K326 and K328 promotes dysinhibition of reconstituted human cardiac thin filaments ACTC1 K326和K328的伪乙酰化促进重构的人心脏细丝的抑制失调。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-22 DOI: 10.1016/j.yjmcc.2025.12.008

Kripa Chitre , Olga E. Karpicheva , Chloe J. King , Michael J. Rynkiewicz , Axel J. Fenwick , John F. Dawson , D. Brian Foster , William Lehman , Anthony Cammarato

Electrostatic interactions between actin residues K326 and K328 and tropomyosin bias tropomyosin to an F-actin location where it blocks myosin attachment. K326/328 acetylation neutralizes their charge, potentially disrupting thin filament-based contractile regulation. We verified acetylation of K326/328 on human cardiac actin (ACTC1) and generated recombinant K326/328Q, pseudo-acetylated ACTC1. Pseudo-acetylation reduced inhibition of myosin-driven motility of F-actin-tropomyosin and F-actin-tropomyosin-troponin at low Ca²⁺. Cryo-EM-based and computational modeling revealed that pseudo-acetylation did not alter tropomyosin positioning along F-actin but decreased local F-actin-tropomyosin interaction energy. Thus, by reducing the energetic demands required for myosin to displace tropomyosin, ACTC1 K326/328 acetylation may promote contractile activation.

肌动蛋白残基K326和K328与原肌凝蛋白之间的静电相互作用使原肌凝蛋白偏向于阻止肌凝蛋白附着的f -肌动蛋白位置。K326/328乙酰化中和了它们的电荷，潜在地破坏了基于细丝的收缩调节。我们验证了K326/328在人心脏肌动蛋白（ACTC1）上的乙酰化，并生成了重组K326/328Q，伪乙酰化ACTC1。在低Ca2+条件下，伪乙酰化降低了肌凝蛋白驱动的f -肌动蛋白-原肌凝蛋白和f -肌动蛋白-原肌凝蛋白-肌钙蛋白的抑制作用。基于冷冻电镜和计算模型显示，伪乙酰化不会改变原肌凝蛋白沿f -肌动蛋白的定位，但会降低局部f -肌动蛋白-原肌凝蛋白相互作用能。因此，通过减少肌凝蛋白取代原肌凝蛋白所需的能量需求，ACTC1 K326/328乙酰化可能促进收缩激活。

引用次数: 0

Corrigendum to ‘Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis’ [Journal of Molecular and Cellular Cardiology 210 (2025) 127–136] “小规模siRNA筛选显示WWC2是心肌细胞有丝分裂的新调节剂”的勘误表[Journal of Molecular and Cellular Cardiology 210(2025) 127-136]。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-21 DOI: 10.1016/j.yjmcc.2025.12.007

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 , Verena Höffken , Joachim Kremerskothen , Rita C.R. Perlingeiro , Jop H. van Berlo

引用次数: 0

Biosensors reveal subcellular redox status in live cells 生物传感器揭示活细胞的亚细胞氧化还原状态

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-20 DOI: 10.1016/j.yjmcc.2025.12.009

Haoqi Li , Huimin Li , Yufan Chao , Yaozhao Li , Zijie Cheng , Yuqing Li , Yun Yin , Tao Chen , Xin Dong , Dan Wu , Qingxun Hu

Redox homeostasis is crucial for cellular function and signaling, with its disruption linked to various diseases. Given the compartment-specific nature of redox regulation, we employed highly responsive genetically encoded fluorescent sensors, including Hyper7, iNap, and roGFP2, to achieve real-time in situ tracking of the redox dynamics of H₂O₂, NADPH and GSH in the cytoplasm and mitochondria. It revealed that glycolysis and oxidative phosphorylation differentially modulate redox metabolites across subcellular domains, demonstrating metabolic pathway-specific regulation of redox equilibrium. Pathological modeling (cardiac hypertrophy, ischemia-reperfusion and cuproptosis) characterized mitochondrial redox systems exhibit superior stress-responsive regulation versus cytoplasmic counterparts, displaying enhanced dynamic responses during injury progression. These results suggest that precise subcellular redox mapping delivers critical insights into dynamic signal transduction mechanisms and proposes targeted therapeutic avenues for redox-associated pathologies through compartment-specific interventions.

氧化还原稳态对细胞功能和信号传导至关重要，其破坏与各种疾病有关。考虑到氧化还原调控的室特异性，我们采用了高响应的遗传编码荧光传感器，包括Hyper7、iNap和roGFP2，来实现对细胞质和线粒体中H2O2、NADPH和GSH氧化还原动力学的实时原位跟踪。研究表明，糖酵解和氧化磷酸化对氧化还原代谢产物在亚细胞结构域的差异调节，证明了氧化还原平衡的代谢途径特异性调节。病理模型（心脏肥厚、缺血-再灌注和铜变）表征线粒体氧化还原系统表现出优于细胞质对应系统的应激反应调节，在损伤进展过程中表现出增强的动态反应。这些结果表明，精确的亚细胞氧化还原图谱为动态信号转导机制提供了重要见解，并通过区室特异性干预为氧化还原相关病理提供了靶向治疗途径。

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引用次数: 0