Journal of molecular and cellular cardiology plus最新文献

SARS-CoV-2-infected cardiomyocytes exhibit upregulated necroptosis, but no evidence of mitochondrial permeability transition sars - cov -2感染的心肌细胞表现出上调的坏死下垂，但没有证据表明线粒体通透性转变

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-19 DOI: 10.1016/j.jmccpl.2025.100833

C. Gross , S. Chatterjee , B.E. Nilsson-Payant , S.D. Stojanović , H. Kefalakes , C. Bär , T. Thum , T. Pietschmann , J. Bauersachs , G. Amanakis

Cardiac involvement in patients infected with COVID-19, in terms of myocarditis and troponin release, is associated with higher mortality. However, the underlying mechanisms are poorly understood.

Infection of cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) with a wild-type variant of SARS-CoV-2 exhibited a cardiotoxic effect. We examined whether elevated intramitochondrial calcium causes opening of the mitochondrial permeability transition pore (mPTP) leading to cell death. The mPTP inhibitor Cyclosporine A (CsA) did not improve viability, and phosphorylation levels of pyruvate dehydrogenase (PDH) remained similar pre- and post-infection, likely suggesting no substantial alteration of the intramitochondrial calcium level. Also, the protein expression of mitochondrial respiratory complexes did not change after SARS-CoV-2 infection.

Next, we examined whether cell death is related to necroptosis or pyroptosis upregulation. The phosphorylation level of receptor-interacting protein kinase 3 (RIP3) was elevated post-infection with SARS-CoV-2 while phosphorylation of mixed lineage kinase domain (MLKL)-S358 remained unaltered. This pattern may point toward an alternative regulation of necroptosis. Chemical inhibition of necroptosis (Necrostatin-1) and pyroptosis (MCC950) did not confer any protection. Notably, the phosphorylation of RIP3 under Necrostatin-1 was still elevated, suggesting that autophosphorylation of RIP3 may be a possible confounder.

Our data suggest that SARS-CoV-2 compromises cell viability in iPSC-CMs and may engage in non-canonical signaling via RIP3 phosphorylation. The lack of MLKL activation and the absence of protective effects from CsA indicate that neither classical necroptosis nor mitochondrial permeability transition are likely to be central regulators of cell death.

就心肌炎和肌钙蛋白释放而言，COVID-19感染患者的心脏受累与更高的死亡率相关。然而，人们对其潜在机制知之甚少。用SARS-CoV-2野生型变体感染人诱导多能干细胞（iPSC-CMs）衍生的心肌细胞表现出心脏毒性作用。我们研究了线粒体内钙升高是否会导致线粒体通透性过渡孔（mPTP）打开，从而导致细胞死亡。mPTP抑制剂环孢素A （Cyclosporine A, CsA）并没有提高存活能力，并且感染前后丙酮酸脱氢酶（PDH）的磷酸化水平保持相似，这可能表明线粒体内钙水平没有实质性改变。此外，线粒体呼吸复合物蛋白表达在SARS-CoV-2感染后未发生变化。接下来，我们研究了细胞死亡是否与坏死或焦亡上调有关。受体相互作用蛋白激酶3 （RIP3）的磷酸化水平在感染SARS-CoV-2后升高，而混合谱系激酶结构域(MLKL)-S358的磷酸化水平保持不变。这种模式可能指向坏死下垂的另一种调节。化学抑制坏死性下垂（Necrostatin-1）和焦亡（MCC950）没有任何保护作用。值得注意的是，在Necrostatin-1作用下，RIP3的磷酸化水平仍然升高，这表明RIP3的自磷酸化可能是一个可能的混杂因素。我们的数据表明，SARS-CoV-2会损害iPSC-CMs中的细胞活力，并可能通过RIP3磷酸化参与非典型信号传导。MLKL缺乏激活和CsA缺乏保护作用表明，经典坏死性坏死和线粒体通透性转变都不可能是细胞死亡的主要调节因子。

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引用次数: 0

Metformin alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy 二甲双胍减轻实验性糖尿病心肌病小鼠舒张功能障碍

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-01 DOI: 10.1016/j.jmccpl.2025.100825

Jordan S.F. Chan , Seyed Amirhossein Tabatabaei Dakhili , Nadeen R. Wu , Magnus J. Stenlund , Alexa N. King , Linyue Dong , Indiresh A. Mangra-Bala , Tanin Shafaati , Sally R. Ferrari , Amanda A. Greenwell , Kunyan Yang , Christina T. Saed , Farah Eaton , Keshav Gopal , Gregory R. Steinberg , Jason R.B. Dyck , John R. Ussher

The first line therapy for managing type 2 diabetes (T2D), metformin, has been shown to be cardioprotective in humans and several preclinical models of cardiovascular disease. However, there has been limited interrogation into metformin's effects on diastolic function, a hallmark characteristic of diabetic cardiomyopathy (DbCM), which is becoming increasingly prevalent in people with pre- and early-stage T2D. Accordingly, we aimed to determine the effects of metformin on the pathogenesis of DbCM and hypothesized that treatment with metformin would alleviate diastolic dysfunction in mice with T2D. To induce experimental T2D and DbCM, male C57BL/6J mice were fed a high-fat diet for 12.5 weeks, in combination with a single, low-dose injection of streptozotocin (75 mg/kg) at week 4.5. The animals' drinking water was randomized to include either vehicle control or metformin (3.0 g/L) during the final 7.5 weeks. As expected, metformin treatment improved glycemia with a trend towards a reduction in adiposity in mice with T2D. Using ultrasound echocardiography, we observed that metformin improved diastolic function in mice with T2D as reflected by an increase and a decrease in the e′/a′ and E/e′ ratios, respectively. Furthermore, wheat-germ agglutinin staining indicated that treatment with metformin decreased cardiomyocyte hypertrophy in mice with T2D. However, mice with T2D treated with metformin did not exhibit increases in myocardial adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Thus, our findings suggest that metformin has salutary actions against DbCM and its associated diastolic dysfunction, which may be independent of its ability to increase AMPK activity.

治疗2型糖尿病（T2D）的一线疗法二甲双胍已被证明对人类和几种心血管疾病的临床前模型具有心脏保护作用。然而，二甲双胍对舒张功能影响的研究有限，舒张功能是糖尿病性心肌病（DbCM）的一个标志性特征，在t2dm前期和早期患者中越来越普遍。因此，我们旨在确定二甲双胍对DbCM发病机制的影响，并假设二甲双胍治疗可以减轻T2D小鼠的舒张功能障碍。为诱导实验性T2D和DbCM，雄性C57BL/6J小鼠12.5周高脂饲粮，4.5周单次低剂量注射链脲佐菌素（75 mg/kg）。在最后7.5周内，将动物的饮用水随机分为对照组和二甲双胍（3.0 g/L）。正如预期的那样，二甲双胍治疗改善了t2dm小鼠的血糖，并有减少肥胖的趋势。通过超声心动图，我们观察到二甲双胍改善了T2D小鼠的舒张功能，反映在e ‘ /a ’和e /e '比值分别增加和减少。此外，小麦胚芽凝集素染色表明，二甲双胍治疗可减少T2D小鼠心肌细胞肥大。然而，二甲双胍治疗的T2D小鼠心肌腺苷单磷酸活化蛋白激酶（AMPK）磷酸化并未增加。因此，我们的研究结果表明，二甲双胍对DbCM及其相关的舒张功能障碍有有益的作用，这可能独立于其增加AMPK活性的能力。

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引用次数: 0

Mitochondrial metabolic remodeling and multi-omics profiling identify plasma biomarkers of myocardial infarction 线粒体代谢重塑和多组学分析鉴定心肌梗死的血浆生物标志物

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-01 DOI: 10.1016/j.jmccpl.2025.100827

Selvam Paramasivan , Mitchell C. Lock , Roberto A. Barrero , Paul C. Mills , Janna L. Morrison , Pawel Sadowski

Mitochondrial dysfunction is a hallmark of myocardial infarction (MI), yet the molecular mechanisms linking metabolic reprogramming in the ischemic myocardium to systemic biomarker signatures remain incompletely understood. In this study, we employed a data-independent acquisition mass spectrometry (SWATH-MS) strategy integrating multi-omics analysis with upstream regulatory network analysis to investigate mitochondrial energy pathway alterations in a preclinical ovine model of MI. Proteomic profiling of infarcted myocardium revealed a pronounced shift from oxidative phosphorylation to glycolysis, accompanied by coordinated suppression of mitochondrial fatty acid β-oxidation enzymes. This metabolic reprogramming was strongly associated with four upstream master regulators, most notably predicted inhibition and significant transcriptional downregulation of PPARGC1A, a key coactivator of mitochondrial biogenesis and oxidative metabolism, indicating disrupted mitochondrial energy homeostasis and impaired adaptive responses in ischemic cardiomyocytes. Parallel plasma proteomic analysis identified a distinct panel of differentially expressed proteins enriched in pathways related to carbon metabolism, amino acid biosynthesis, and cardiac muscle contraction. Notably, mitochondrial metabolic enzymes such as SUCLG1, MDH2, HADHA, and HADHB were significantly downregulated at both the transcript and protein levels in cardiac tissue, while their protein abundance was markedly increased in plasma post-MI, highlighting their potential as circulating biomarkers of mitochondrial dysfunction. These findings provide mechanistic insight into the energy metabolic remodeling that occurs during myocardial ischemic injury and establish a systems-level framework for linking tissue-specific mitochondrial alterations with accessible plasma biomarkers. This study supports the translational potential of targeting mitochondrial pathways for diagnostic and therapeutic strategies in ischemic heart disease.

线粒体功能障碍是心肌梗死（MI）的一个标志，然而，将缺血心肌中的代谢重编程与全身生物标志物特征联系起来的分子机制仍不完全清楚。在这项研究中，我们采用了数据独立采集质谱（SWATH-MS）策略，将多组学分析与上游调控网络分析相结合，研究了绵羊心肌梗死模型中线粒体能量途径的改变。梗死心肌的蛋白质组学分析显示，心肌梗死从氧化磷酸化到糖酵解发生了明显的转变，并伴有线粒体脂肪酸β-氧化酶的协同抑制。这种代谢重编程与四个上游主调控因子密切相关，最显著的预测是PPARGC1A的抑制和显著的转录下调，PPARGC1A是线粒体生物发生和氧化代谢的关键共激活因子，表明缺血心肌细胞线粒体能量稳态被破坏，适应性反应受损。平行血浆蛋白质组学分析发现，在碳代谢、氨基酸生物合成和心肌收缩相关的途径中富集了一组不同的差异表达蛋白。值得注意的是，心肌组织中SUCLG1、MDH2、HADHA和HADHB等线粒体代谢酶的转录物和蛋白水平均显著下调，而心肌梗死后血浆中这些酶的蛋白丰度显著增加，这凸显了它们作为线粒体功能障碍循环生物标志物的潜力。这些发现为心肌缺血损伤期间发生的能量代谢重塑提供了机制见解，并建立了将组织特异性线粒体改变与可获得的血浆生物标志物联系起来的系统级框架。这项研究支持了靶向线粒体途径在缺血性心脏病诊断和治疗策略中的转化潜力。

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引用次数: 0

Impaired PGC-1α-pAMPK signaling in postmenopausal women undergoing cardiac surgery and the role of nicotinamide in its reversal: Insights from a murine model 绝经后妇女心脏手术后PGC-1α-pAMPK信号受损及烟酰胺在其逆转中的作用：来自小鼠模型的见解

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-01 DOI: 10.1016/j.jmccpl.2025.100831

Mark Robitaille , Usman Ahmed , Juan Valencia , Adnan Khan , Adil al-Karim Manji , Elizabeth Russ , Louis Chu , Kamal Khabbaz , Feroze Mahmood , Robina Matyal

Postmenopausal women undergoing cardiac surgery face disproportionately worse outcomes compared with men, a disparity linked to mitochondrial dysfunction following estrogen loss. We investigated sex-specific metabolic responses to cardiac stress in surgical patients and in a murine model of postmenopausal dysfunction, with a focus on proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling and the therapeutic potential of nicotinamide (NAM), a precursor of nicotinamide adenine dinucleotide (NAD⁺). In a prospective cohort of 102 patients (51 men, 51 women) undergoing cardiac surgery with cardiopulmonary bypass, women exhibited a significantly higher incidence of diastolic dysfunction and longer hospital stays despite comparable baseline characteristics. Molecular analysis of atrial tissue revealed that men demonstrated increased postoperative PGC-1α and phosphorylated AMP-activated protein kinase (pAMPK), while women had reduced expression and also displayed a significant decline in myocardial NAD⁺ levels. To mechanistically model these findings, ovariectomized mice on a high-fat diet exhibited reduced myocardial PGC-1α and pAMPK expression, suppressed antioxidant defenses, and increased fibrosis. NAM supplementation restored myocardial NAD⁺, increased PGC-1α expression, and significantly improved systolic and diastolic cardiac function. These findings indicate that loss of estrogen impairs responses to oxidative stress in postmenopausal women, predisposing to adverse outcomes after cardiac stress. NAM may represent a promising non-hormonal strategy to restore mitochondrial function and improve cardiac function. This supports further evaluation of NAD⁺-boosting therapies as targeted interventions for postmenopausal women at risk of heart failure with preserved ejection fraction.

绝经后接受心脏手术的女性与男性相比面临着不成比例的更差的结果，这种差异与雌激素丢失后的线粒体功能障碍有关。我们研究了外科手术患者和绝经后功能障碍小鼠模型对心脏应激的性别特异性代谢反应，重点关注增殖激活受体γ辅助激活因子1- α (PGC-1α)信号传导和烟酰胺（NAM）的治疗潜力，烟酰胺腺嘌呤二核苷酸（NAD+）的前体。在102例接受心脏手术合并体外循环的患者（51例男性，51例女性）的前瞻性队列研究中，尽管具有相似的基线特征，但女性的舒张功能障碍发生率明显更高，住院时间更长。心房组织分子分析显示，男性术后PGC-1α和磷酸化amp活化蛋白激酶（pAMPK）升高，而女性心肌NAD+水平明显下降。为了对这些发现进行机制模拟，切除卵巢的小鼠在高脂肪饮食中表现出心肌PGC-1α和pAMPK表达降低，抗氧化防御受到抑制，纤维化增加。补充NAM恢复心肌NAD+，增加PGC-1α表达，显著改善心脏收缩和舒张功能。这些研究结果表明，雌激素的丧失会损害绝经后妇女对氧化应激的反应，易导致心脏应激后的不良后果。NAM可能代表了一种有希望的非激素策略来恢复线粒体功能和改善心功能。这支持进一步评估NAD+增强疗法作为有射血分数保留的绝经后心力衰竭风险妇女的靶向干预措施。

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引用次数: 0

Insulin use promotes pro-inflammatory changes in the transcriptome of atherosclerotic plaques in patients with diabetes mellitus 胰岛素使用促进糖尿病患者动脉粥样硬化斑块转录组的促炎改变

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-01 DOI: 10.1016/j.jmccpl.2025.100829

Angelle Bradford , Tadashi Yoshida , Sergiy Sukhanov , Foster F. Woods , Patrice Delafontaine , Hernan A. Bazan , T. Cooper Woods

Background

Diabetes Mellitus is associated with increased risk of myocardial infarctions and strokes due to accelerated atherosclerotic plaque development and rupture. The mechanisms driving plaque rupture in the diabetic setting remain unclear.

Methods

We sequenced ribosome-depleted total RNA from carotid plaques obtained from diabetic subjects undergoing carotid endarterectomy with high-grade stenosis, who either recently experienced a carotid-related ischemic cerebrovascular event (Symptomatic, n = 6) or had no such event (Asymptomatic, n = 6).

Results

Principal component analysis of the most variable transcripts demonstrated that sex and insulin use, rather than plaque rupture status, were the major contributors to the variability in the dataset. Hierarchical clustering further highlighted the importance of these factors in the dataset but also included two clusters whose expression was elevated in the symptomatic group. These clusters were enriched with transcripts for immunoglobulins and matrix metalloproteinases, suggesting increased B-cell infiltration and extracellular matrix degradation in the symptomatic plaques. We identified only two transcripts, RNU2–1 and PI4KAP1, as significantly up-regulated in the symptomatic group. We identified 35 transcripts with altered expression in subjects on insulin therapy, including regulators of B-cells (MZB1), T cells (BTN3A1, BTN3A2, BTN3A3, CD96, and CTSW), and macrophages (MPEG1). Next, we used spatial deconvolution to focus on differentially expressed genes in the fibrous cap of the carotid plaques. In the symptomatic group, we identified elevated levels of five angiogenesis-associated transcripts (ALS2CL, EPHB4, SMAD1, PREX2, EFNA5), suggesting increased intraplaque neovascularization in ruptured plaques.

Conclusions

Thus, insulin use significantly impacts the transcriptome of atherosclerotic plaques, promoting vascular inflammation.

背景：由于动脉粥样硬化斑块的加速发展和破裂，糖尿病与心肌梗死和中风的风险增加有关。糖尿病患者斑块破裂的机制尚不清楚。方法：我们对接受颈动脉内膜切除术并伴有高度狭窄的糖尿病患者颈动脉斑块中核糖体缺失的总RNA进行测序，这些患者近期经历过颈动脉相关的缺血性脑血管事件（有症状的，n = 6）或没有发生过此类事件（无症状的，n = 6）。结果对最可变转录本的主成分分析表明，性别和胰岛素使用，而不是斑块破裂状态，是数据集中可变性的主要因素。分层聚类进一步强调了这些因素在数据集中的重要性，但也包括两个在症状组中表达升高的聚类。这些团簇富含免疫球蛋白和基质金属蛋白酶的转录本，表明有症状斑块中b细胞浸润和细胞外基质降解增加。我们发现只有两个转录本RNU2-1和PI4KAP1在症状组中显著上调。我们在胰岛素治疗的受试者中发现了35个表达改变的转录本，包括b细胞（MZB1）、T细胞（BTN3A1、BTN3A2、BTN3A3、CD96和CTSW）和巨噬细胞（MPEG1）的调节因子。接下来，我们使用空间反褶积来关注颈动脉斑块纤维帽中的差异表达基因。在有症状组，我们发现5种血管生成相关转录物（ALS2CL、EPHB4、SMAD1、PREX2、EFNA5）水平升高，表明破裂斑块斑块内新生血管增加。因此，胰岛素使用显著影响动脉粥样硬化斑块的转录组，促进血管炎症。

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引用次数: 0

Identification of circular RNA hsa-PHACTR4_0009 as a new class of biomarker for transposition of the great arteries 环状RNA hsa-PHACTR4_0009作为一类新的大动脉转位生物标志物的鉴定

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-12-01 DOI: 10.1016/j.jmccpl.2025.100830

Neha Rawal , Anmol Gurgela , Snigdha Kumari , Manoj Kumar Rohit , Ajay Bahl , Anupam Mittal

Dextro-Transposition of great arteries (d-TGA) is a cardiac birth anomaly with reversed anatomic position of the aorta and pulmonary artery, with a poor prognosis. The molecular aetiology of d-TGA remains elusive, possibly due to polygenic contributions and gene-environment interactions, suggesting the role of epigenetic components in d-TGA. Various non-coding RNAs, like circular RNA (circRNA), epigenetically regulate gene expression and may also serve as putative biomarkers because of their exceptionally high stability in plasma. In this study, we performed whole transcriptome analysis in the plasma of diseased and healthy neonates to identify circular RNA specifically dysregulated in the d-TGA condition. Our data suggested that a circular RNA, i.e., hsa-PHACTR4_0009, is significantly increased in the plasma of d-TGA neonates and has 85 % sensitivity and 80 % specificity with an AUC value of 0.900 with foetal echocardiography as the gold standard. Interestingly, d-TGA cases had a proportional increase of hsa-PHACTR4_0009 with the severity of the disease, as evident by comparably high levels in patients with intact interventricular and interatrial septa. Transcriptomics analysis further indicated that there is a dysregulation of the focal adhesion assembly genes like vimentin, profilin, gamma-actin and emerin, corroborating with hsa-PHACTR4_0009 expression. Notably, overexpression of hsa-PHACTR4_0009 led to increased cell migration in H9C2 cells, suggesting that defects in cell migration are involved in the development of d-TGA. Collectively, our study suggests hsa-PHACTR4_0009 as a potential biomarker of d-TGA and provides a highly valuable insight into the molecular pathogenesis of d-TGA from an unexplored perspective, enabling a better prognosis for these patients.

右大动脉转位（d-TGA）是一种心脏出生异常，主动脉和肺动脉解剖位置相反，预后较差。d-TGA的分子病因尚不清楚，可能是由于多基因的贡献和基因与环境的相互作用，这表明表观遗传成分在d-TGA中的作用。各种非编码RNA，如环状RNA (circRNA)，在表观遗传上调节基因表达，也可能作为假定的生物标志物，因为它们在血浆中具有异常高的稳定性。在这项研究中，我们对患病和健康新生儿的血浆进行了全转录组分析，以鉴定在d-TGA条件下特异性失调的环状RNA。我们的数据表明，环状RNA，即hsa-PHACTR4_0009，在d-TGA新生儿血浆中显著增加，具有85%的敏感性和80%的特异性，以胎儿超声心动图为金标准的AUC值为0.900。有趣的是，d-TGA患者的hsa-PHACTR4_0009与疾病的严重程度成比例增加，在完整的室间隔和房间隔患者中，hsa-PHACTR4_0009的水平相对较高。转录组学分析进一步表明，局灶黏附组装基因vimentin、profilin、γ -actin、emerin表达异常，与hsa-PHACTR4_0009表达一致。值得注意的是，hsa-PHACTR4_0009的过表达导致H9C2细胞迁移增加，这表明细胞迁移缺陷参与了d-TGA的发展。总之，我们的研究表明hsa-PHACTR4_0009可能是d-TGA的潜在生物标志物，并从未被探索的角度对d-TGA的分子发病机制提供了非常有价值的见解，使这些患者能够更好地预后。

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引用次数: 0

Persistently increased CaMKIIδ autophosphorylation mediates pathologic SR Ca loss in a murine model of Doxorubicin-induced cardiomyopathy 在阿霉素诱导的心肌病小鼠模型中，持续增加的CaMKIIδ自磷酸化介导病理性SR Ca丢失

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-21 DOI: 10.1016/j.jmccpl.2025.100828

Anna-Lena Feder , Daniel Tarnowski , Anna-Maria Pfützenreuter , Maria Johanna Baier , Julian Mustroph , Maithily S. Nanadikar , Dörthe M. Katschinski , Lars Siegfried Maier , Can Martin Sag

Background

Doxorubicin (DOX)-induced cardiomyopathy (DICM) manifests as left ventricular (LV) systolic dysfunction. DOX triggers oxidative stress and CaMKIIδ activity in cardiac myocytes. CaMKIIδ activation leads to impaired intracellular Ca handling and contractile dysfunction because of pathologic Ca loss from the sarcoplasmic reticulum (SR). While CaMKIIδ is canonically activated by autophosphorylation, it can also be activated via oxidation.

Objectives

We aimed to investigate the predominant mode of CaMKIIδ activation in DICM.

Methods

We utilized two transgenic mouse models, one lacking CaMKIIδ (CaMKIIδ^−/−) and a “redox-dead” CaMKIIδ^Val281/282 model. Acute changes in intracellular Ca handling and CaMKIIδ activation status were examined following 15 min of DOX exposure. Long-term effects were studied in CaMKIIδ^−/− mice (vs. CaMKIIδ^+/+ wildtype littermates) and redox-dead CaMKIIδ^Val281/282 mice (vs. CaMKIIδ^Met281/282 wildtype littermates) that underwent DOX treatment in-vivo. Cardiac function (via echocardiography), intracellular Ca handling, and CaMKIIδ-related signaling were assessed 12 weeks post-treatment.

Results

DOX acutely increased CaMKIIδ activity by autophosphorylation and oxidation in both WT lines, while autophosphorylated CaMKIIδ was still detected in CaMKIIδ^Val281/282 mice, which resulted in comparably increased SR Ca leakage mediated by CaMKII-dependent RyR2-hyperphosphorylation at pS2814 in all aforementioned groups. In contrast, pharmacological and genetic inhibition of CaMKIIδ (i.e. in CaMKIIδ^−/−) prevented DOX-induced CaMKIIδ-hyperactivation, RyR2-hyperphosphorylation and SR Ca loss. Similarly, only CaMKIIδ^−/− mice were protected from long-term DOX-induced LV dysfunction in-vivo. Redox-dead CaMKIIδ^Val281/282 mice exhibited similar LV dysfunction as WT littermates, with persistent CaMKIIδ autophosphorylation, subsequent RyR2 hyperphosphorylation, and increased CaMKIIδ-dependent SR Ca leakage.

Conclusions

Persistently increased CaMKIIδ autophosphorylation, but not oxidation, mediates pathologic SR Ca loss in Doxorubicin-induced cardiomyopathy.

多柔比星（DOX）诱导的心肌病（DICM）表现为左心室（LV）收缩功能障碍。DOX触发心肌细胞氧化应激和CaMKIIδ活性。CaMKIIδ活化导致细胞内钙处理受损和肌浆网（SR）病理性钙损失导致收缩功能障碍。虽然CaMKIIδ通常通过自磷酸化激活，但它也可以通过氧化激活。目的探讨DICM中CaMKIIδ的主要激活模式。方法采用两种转基因小鼠模型，一种是缺乏CaMKIIδ (CaMKIIδ−/−)，另一种是氧化还原-死亡CaMKIIδ val281 /282模型。在DOX暴露15分钟后，检测细胞内Ca处理和CaMKIIδ激活状态的急性变化。研究了在体内接受DOX处理的CaMKIIδ−/−小鼠（与CaMKIIδ+/+野生型幼崽相比）和氧化还原死亡的CaMKIIδ val281 /282小鼠（与CaMKIIδ met281 /282野生型幼崽相比）的长期影响。治疗后12周评估心功能（通过超声心动图）、细胞内钙处理和camkii δ相关信号。结果dox在两种WT系中均通过自磷酸化和氧化作用急剧增加CaMKIIδ活性，而在CaMKIIδ val281 /282小鼠中仍检测到自磷酸化的CaMKIIδ，这导致上述所有组中由camkii依赖性ryr2 -过磷酸化介导的pS2814 SR Ca泄漏相对增加。相比之下，CaMKIIδ的药理学和遗传抑制（即CaMKIIδ−/−）阻止了dox诱导的CaMKIIδ-过度活化、ryr2 -过度磷酸化和SR Ca丢失。同样，只有CaMKIIδ−/−小鼠在体内免受dox诱导的长期左室功能障碍的保护。氧化还原死亡的CaMKIIδ val281 /282小鼠表现出与WT幼崽相似的左室功能障碍，持续的CaMKIIδ自磷酸化，随后的RyR2过度磷酸化，以及CaMKIIδ依赖的SR Ca泄漏增加。结论持续增加的CaMKIIδ自磷酸化，而不是氧化，介导了阿霉素诱导的心肌病的病理性SR Ca丢失。

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引用次数: 0

Cardiomyocyte Rac1 signaling in hypertrophy, arrhythmia, and cardiac stress adaptation 心肌细胞Rac1信号在肥厚、心律失常和心脏应激适应中的作用

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-14 DOI: 10.1016/j.jmccpl.2025.100826

James P. Teuber , Rachel E. Scissors , Matthew J. Brody

Cardiovascular disease remains the leading cause of mortality globally and is often marked by pathologic cardiac remodeling including hypertrophy and fibrosis that promote the progression to heart failure. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho family small GTPase that acts as a molecular switch to regulate signaling pathways that contribute to cardiac development, hypertrophy, arrhythmia, and stress adaptation. Active Rac1 promotes cardiomyocyte hypertrophy in vitro and in vivo whereas genetic ablation or expression of inactive Rac1 protects against cardiomyocyte hypertrophy. Rac1 activates mitogen-activated protein kinase (MAPK) cascades and its canonical effector, p21-activated kinase 1 (PAK1), to promote hypertrophic gene expression. Additionally, Rac1 is a requisite accessory subunit required to activate the reactive oxygen species (ROS)-generating NADPH oxidase-2 (NOX2) enzyme complex that in turn induces hypertrophic redox signaling and oxidative damage. Cardiomyocyte Rac1 activity plays an indispensable function in cardiac adaption to elevated sympathetic activity. Rac1 cysteine palmitoylation cycling is required to attenuate hyperactive protein kinase A (PKA) signaling in response to acute adrenergic stimulation and in several models of chronic hypertrophic stress. Moreover, Rac1 and its effectors have important roles in cardiomyocyte electrophysiology and arrhythmogenesis and therapeutic approaches directly targeting Rac1, NOX2, PAK1, or apoptosis signal-regulating kinase 1 (ASK1) have shown promise in preclinical models of cardiac disease. Here, we review what is known about Rac1 signaling in cardiomyocytes, discuss how these signaling pathways can potentially be targeted for the treatment and prevention of cardiac disease, and propose areas of Rac1 signaling that warrant further exploration.

心血管疾病仍然是全球死亡的主要原因，通常以病理性心脏重塑为特征，包括肥大和纤维化，从而促进心力衰竭的进展。ras相关C3肉毒毒素底物1 （Rac1）是一种Rho家族小GTPase，作为分子开关调节促进心脏发育、肥厚、心律失常和应激适应的信号通路。活性Rac1在体外和体内促进心肌细胞肥大，而基因消融或非活性Rac1的表达可防止心肌细胞肥大。Rac1激活丝裂原活化蛋白激酶（MAPK）级联及其典型效应物p21活化激酶1 (PAK1)，促进肥厚性基因表达。此外，Rac1是激活活性氧（ROS）生成NADPH氧化酶-2 （NOX2）酶复合物所必需的辅助亚基，从而诱导肥厚氧化还原信号传导和氧化损伤。心肌细胞Rac1活性在心脏适应交感神经活动升高中起着不可或缺的作用。在急性肾上腺素能刺激和几种慢性肥厚应激模型中，需要Rac1半胱氨酸棕榈酰化循环来减弱过度活跃的蛋白激酶A （PKA）信号。此外，Rac1及其效应物在心肌细胞电生理和心律失常发生中发挥重要作用，直接靶向Rac1、NOX2、PAK1或凋亡信号调节激酶1（凋亡信号调节激酶1，ASK1）的治疗方法在心脏病的临床前模型中显示出前景。在这里，我们回顾了关于心肌细胞中Rac1信号传导的已知信息，讨论了这些信号传导途径如何潜在地靶向治疗和预防心脏病，并提出了值得进一步探索的Rac1信号传导领域。

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引用次数: 0

FABP3 and FABP4 promote lipid peroxidation injury during static cold storage of donor heart: Insights from multi-omics and therapeutic targeting FABP3和FABP4促进供体心脏静态冷藏过程中的脂质过氧化损伤：来自多组学和靶向治疗的见解

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-13 DOI: 10.1016/j.jmccpl.2025.100497

Yu Feng , Yongbu Peng , Jincheng Hou , Zihao Wang , Junlin Lai , Tixiusi Xiong , Jiawei Shi , Yixuan Wang , Wai Yen Yim , Yuqi Chen , Nianguo Dong

Objectives

To clarify the mechanism of myocardial injury associated with lipid peroxidation and the role of fatty acid binding proteins FABP3/4 during Static cold storage (SCS) of donor hearts.

Methods

Multi-omics analysis included mouse myocardial metabolomics and transcriptomics, proteomics of cardiac preservation solution in SCS injury. Lipid peroxidation was detected by malondialdehyde, transmission electron microscopy (TEM), and fluorescent probes. Lipid peroxidation antagonist MitoQ was examined by TEM. FABP3/4 were analyzed by combining the proteomic data of first perfusion serum from human donor hearts with those of mouse myocardial SCS solution. Overexpressing FABP3/4 were evaluated by detecting ROS and apoptosis via flow cytometry. snRNA-seq revealed the cellular landscape of SCS injury in pig cardiomyocytes.

Results

Multi-omics analysis of the SCS injury model revealed significant changes in lipid metabolism. Disturbed lipid metabolism and peroxidation were demonstrated in mouse SCS injury model and cell model. MitoQ attenuated lipid peroxidation and antagonized cardiac SCS injury. FABP3/4 were released during SCS and promoted injury in cardiomyocytes. In SCS solution, FABP3/4 expression were improved in both short-term and long-term SCS. In myocardial tissue, FABP3 expression decreased during short-term SCS and then gradually increased after long-term SCS. FABP4 expression were first upregulated and then decreased, remaining stable during long-term SCS. Pig cardiomyocytes showed low FABP3 and high FABP4 expression during short-term SCS.

Conclusion

Disturbed lipid metabolism and peroxidation occur during SCS of hearts. FABP3/4 promote lipid uptake and aggravate SCS damage. FABP3/4 should be further investigated as potential therapeutic targets for SCS injury during heart transplantation.

目的探讨脂质过氧化引起心肌损伤的机制及脂肪酸结合蛋白FABP3/4在供心静态冷藏过程中的作用。方法多组学分析包括小鼠心肌代谢组学、转录组学、心肌保存液蛋白质组学等。采用丙二醛、透射电镜（TEM）和荧光探针检测脂质过氧化。用透射电镜检测脂质过氧化拮抗剂MitoQ。结合人供心首次灌注血清和小鼠心肌SCS溶液的蛋白质组学数据分析FABP3/4。流式细胞术检测ROS和细胞凋亡，评价过表达FABP3/4的小鼠。snRNA-seq揭示了猪心肌细胞SCS损伤的细胞景观。结果对SCS损伤模型进行多组学分析，发现脂质代谢发生显著变化。小鼠SCS损伤模型和细胞模型均出现脂质代谢紊乱和过氧化现象。MitoQ减轻脂质过氧化和拮抗心脏SCS损伤。FABP3/4在SCS过程中释放，促进心肌细胞损伤。在SCS溶液中，FABP3/4的表达在短期和长期SCS中均有提高。在心肌组织中，FABP3的表达在短期SCS期间降低，在长期SCS后逐渐升高。FABP4表达先上调后降低，在长期SCS中保持稳定。短期SCS期间，猪心肌细胞FABP3低表达，FABP4高表达。结论心脏SCS存在脂质代谢紊乱和过氧化作用。FABP3/4促进脂质摄取，加重SCS损伤。应进一步研究FABP3/4作为心脏移植过程中SCS损伤的潜在治疗靶点。

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引用次数: 0

Cancer-driven cytokine immunomodulation ameliorates cardiac function and suppresses fibrosis 癌症驱动的细胞因子免疫调节改善心功能和抑制纤维化

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-12 DOI: 10.1016/j.jmccpl.2025.100493

Laris Achlaug , Lama Awwad , Irina Langier Goncalves , Sharon Aviram , Ariella Glasner , Ami Aronheim

Heart failure remains a leading cause of morbidity and mortality worldwide, with limited progress in the development of novel therapies. It has been demonstrated that tumor growth improves cardiac function and reduces myocardial fibrosis in mouse models of heart failure. It is clear that cancer cell implantation is not a possible therapeutic strategy for heart failure. Therefore, we further studied the underlying mechanism involved, with the objective of demonstrating its broad therapeutic applicability. We show that a single intravenous injection of serum from tumor-bearing mice rapidly augments left-ventricular fractional shortening and suppresses fibrosis in the heart, diaphragm, and skeletal muscles. Cytokine profiling identified IFNγ and TNFα as essential mediators secreted downstream of natural killer (NK) cell activation. Purified recombinant IFNγ and TNFα mimic the serum effect, polarizing cardiac and skeletal macrophages toward an anti-inflammatory, reparative state. We further show that macrophage depletion abrogates the observed beneficial effect, confirming their critical role. Our findings define a novel NK cell–macrophage cytokine axis that reverses cardiac dysfunction and fibrosis in pressure-overload (transverse aortic constriction) and ATF3-transgenic heart failure models. Together, these findings define a novel host-tumor microenvironment response through cytokine secretion, which leads to cardiac repair and dissolution of fibrosis. This work presents a novel therapeutic strategy for harnessing innate immune cells in the treatment of heart failure and fibrotic disease.

心力衰竭仍然是世界范围内发病率和死亡率的主要原因，在开发新疗法方面进展有限。在心力衰竭小鼠模型中，已经证明肿瘤生长可以改善心功能并减少心肌纤维化。很明显，癌细胞植入不是心力衰竭的一种可能的治疗策略。因此，我们进一步研究了相关的潜在机制，目的是证明其广泛的治疗适用性。我们的研究表明，单次静脉注射荷瘤小鼠血清可迅速增加左心室缩短，并抑制心脏、膈肌和骨骼肌的纤维化。细胞因子分析发现IFNγ和TNFα是自然杀伤（NK）细胞激活下游分泌的重要介质。纯化重组IFNγ和TNFα模拟血清效应，极化心脏和骨骼巨噬细胞走向抗炎、修复状态。我们进一步表明，巨噬细胞耗竭抵消了观察到的有益作用，证实了它们的关键作用。我们的研究结果定义了一种新的NK细胞-巨噬细胞细胞因子轴，可以逆转压力过载（主动脉横缩）和atf3转基因心力衰竭模型中的心功能障碍和纤维化。总之，这些发现定义了一种新的宿主-肿瘤微环境反应，通过细胞因子分泌，导致心脏修复和纤维化溶解。这项工作提出了一种利用先天免疫细胞治疗心力衰竭和纤维化疾病的新治疗策略。

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引用次数: 0