Journal of molecular and cellular cardiology plus最新文献_第2页

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

Coxsackie and adenovirus receptor is a novel regulator of inflammatory response in endotoxin-induced failing heart. 柯萨奇和腺病毒受体是内毒素诱导心力衰竭炎症反应的一种新的调节因子。

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-06 DOI: 10.1016/j.jmccpl.2025.100496

Reo Matsumura , Mototsugu Nishii , Haruya Usuku , Masahiro Nakayama , Masaki Hachisuka , Naho Misawa , Ryo Saji , Fumihiro Ogawa , Alan Valaperti , Yoshihiro Ishikawa , Ichiro Takeuchi

The regulatory mechanisms for inflammatory response in the heart to endotoxin, which causes severe cardiac dysfunction, are not fully understood. We hypothesized the involvement of coxsackie and adenovirus receptor (CXADR), which can promote tissue inflammation by potentiating cell-cell adhesion, independent of viral infection, and examined the role of CXADR in endotoxin-induced cardiac dysfunction and its mechanism using an experimental mouse model. Conditional whole-body and endothelium-specific CXADR knockout (W-KO and E-KO, respectively) mice were generated using the Cre-loxP system and administered lipopolysaccharide (LPS) or vehicle alone, like wild-type (WT) mice. Cardiac CXADR increased 12 h after LPS challenge in WT mice, along with improved cardiac dysfunction and reduced cardiac expression of interleukin (IL)-6 and IL-1β. Moreover, W-KO in adult mice worsened cardiac dysfunction and increased expression of these cytokines. Meanwhile, E-KO exhibited the opposite effects, concomitantly reducing myocardial inflammation. Bulk RNA sequencing analysis identified an enriched IL-17 A signaling pathway capable of inducing IL-6 and IL-1β expression in the heart 12 h after LPS challenge. In this heart, E-KO attenuated phosphorylation of p38 but not of upstream mitogen-activated protein kinase kinase (MKK)3/6. Conversely, W-KO augmented phosphorylation of p38, MKK3/6, and NF-κB/p65, which are key drivers of the IL-17 A signaling. Our study is the first to demonstrate that increased CXADR expression plays a dual role as both a pro-inflammatory mediator and an anti-inflammatory protector in endotoxin-induced cardiac dysfunction, possibly by positively or negatively regulating p38 activation depending on its cellular origin. Targeted manipulation of CXADR expression may provide clinical benefits.

心脏对内毒素的炎症反应的调节机制，导致严重的心功能障碍，尚不完全清楚。我们假设柯萨奇和腺病毒受体（CXADR）参与其中，它可以通过增强细胞-细胞粘附而促进组织炎症，独立于病毒感染，并通过实验小鼠模型研究了CXADR在内毒素诱导的心功能障碍中的作用及其机制。使用Cre-loxP系统产生条件全身和内皮特异性CXADR敲除（分别为W-KO和E-KO）小鼠，并像野生型（WT）小鼠一样单独给予脂多糖（LPS）或载体。LPS刺激后12小时，WT小鼠心脏CXADR升高，心功能障碍改善，白细胞介素(IL)-6和IL-1β表达降低。此外，成年小鼠的W-KO加重了心功能障碍，增加了这些细胞因子的表达。同时，E-KO表现出相反的作用，同时减少心肌炎症。大量RNA测序分析发现，在LPS刺激后12小时，一个富集的IL-17 A信号通路能够诱导IL-6和IL-1β的表达。在这个心脏中，E-KO减弱了p38的磷酸化，但没有减弱上游丝裂原活化蛋白激酶（MKK）3/6的磷酸化。相反，W-KO增加了p38、MKK3/6和NF-κB/p65的磷酸化，这是il - 17a信号传导的关键驱动因素。我们的研究首次证明，CXADR表达的增加在内毒素诱导的心功能障碍中扮演着促炎介质和抗炎保护剂的双重角色，可能是通过积极或消极地调节p38的激活，这取决于其细胞来源。有针对性地操纵CXADR表达可能提供临床益处。

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引用次数: 0

Signaling pathway alterations in hearts of a porcine model harboring a β-myosin heavy chain (MYH7-R403Q) gene variant 含有β-肌球蛋白重链（MYH7-R403Q）基因变异的猪模型心脏信号通路的改变

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-11-04 DOI: 10.1016/j.jmccpl.2025.100495

Chad M. Warren , David M. Ryba , Gail E. Geist , Aileen Castro Coronado , Beata M. Wolska , Paul H. Goldspink , R. John Solaro

The disease-causing myosin variant (MYH7-403Q) is linked to hypertrophic cardiomyopathy (HCM). We carried out a research study of signaling pathways in heart samples from control wild-type (WT) GE Yucatán mini-pigs and their littermates harboring the gene variant, MYH7-R403Q. Our approach permits the determination of adverse signaling pathways involved in different regions of a translationally relevant heart without the effects of intervention. We examined the left ventricular free wall (LV), endocardium (EN), and coronary arteries (CA) from 5 transgenic and 5 wild-type mini-pig littermates to determine alterations in global phosphorylation and protein abundance. Digested peptides from 6 to 7 months old mixed-sex mini-pigs were isobarically labeled; 95 % were phospho-enriched, and 5 % were used as the unmodified (total) fraction. The phospho-enriched and unmodified fractions were injected into an Orbitrap Fusion Lumos and analyzed using PEAKS Studio and Ingenuity Pathway Analysis. Surprisingly, we found no significant changes in the phospho-peptide and unmodified protein abundances in CA. Compared to WT, both LV and EN samples displayed minor changes in phosphorylation and significant changes in unmodified proteins. Bioinformatic analysis revealed that pathways associated with mechano-signaling between cardiomyocytes and the extracellular matrix and inflammation were altered in LV and EN samples. In addition, EN samples had larger differences in pathways related to metabolic dysfunction compared to LV. Our findings provide a translational understanding of signaling pathways altered in the MYH7-R403Q gene variant.

引起疾病的肌球蛋白变体（MYH7-403Q）与肥厚性心肌病（HCM）有关。我们对携带MYH7-R403Q基因变体的对照野生型（WT） GE Yucatán迷你猪及其窝仔的心脏样本的信号通路进行了研究。我们的方法允许在没有干预影响的情况下确定涉及翻译相关心脏不同区域的不良信号通路。我们检测了5只转基因猪和5只野生型迷你猪的左心室游离壁（LV）、心内膜（EN）和冠状动脉（CA），以确定其整体磷酸化和蛋白质丰度的变化。对6 ~ 7月龄混合型小型猪的消化肽进行等压标记；95%是富磷的，5%是未修饰的（总）部分。将富磷和未修饰的部分注入Orbitrap Fusion Lumos，并使用PEAKS Studio和Ingenuity Pathway Analysis进行分析。令人惊讶的是，我们发现CA的磷酸化肽和未修饰蛋白丰度没有显著变化。与WT相比，LV和EN样品的磷酸化变化较小，未修饰蛋白的变化显著。生物信息学分析显示，在LV和EN样本中，心肌细胞与细胞外基质和炎症之间的机械信号通路发生了改变。此外，与LV相比，EN样本在与代谢功能障碍相关的途径上存在更大的差异。我们的研究结果提供了对MYH7-R403Q基因变异中信号通路改变的翻译理解。

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引用次数: 0

Rab10 plays a protective role in the development of pathological cardiac hypertrophy Rab10在病理性心肌肥厚的发生发展中起保护作用

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-10-31 DOI: 10.1016/j.jmccpl.2025.100494

Fang Xu , Min Wu , Yihan Wang , Haiyan Luo , Xiaobo Gao , Song Lai , Cailing Lu

Prolonged cardiac hypertrophy is a main risk factor for heart failure (HF). During cardiac hypertrophy remodelling, there is an increase in protein synthesis, as well as the trafficking and localization of proteins to their functional sites. Rab GTPases, which are key regulators of vesicular formation, movement, and fusion, play a crucial role in these processes. In this study, we identified Rab10, a small GTPase belonging to the Rab family, as a novel regulator to inhibit cardiac hypertrophy. Cardiomyocyte hypertrophy was induced by Ang II or pressure overload in primary neonatal rat cardiomyocytes (NRCMs) or mouse model. We found that Rab10 expression was downregulated in NRCMs or murine hearts after hypertrophic stress. Rab10 overexpression attenuated cardiomyocyte hypertrophy, whereas its silencing exacerbated the phenotype, demonstrating its essential antihypertrophic role in vitro. To determine the in vivo role of Rab10 in the heart, we generated cardiac-specific Rab10-overexpressing transgenic mice (TG). When subjected to Ang II infusion or pressure overload, Rab10 TG mice displayed an improved contractile function and attenuated hypertrophic remodelling. In contrast, AAV9-mediated cardiac-specific knockdown of Rab10 significantly aggravated pressure overload-induced cardiomyocyte hypertrophy. Mechanically, Rab10 suppressed the phosphorylation of ERK1/2 and AKT, thereby attenuating the development cardiac hypertrophy. Additionally, we demonstrated that Rab10 was post-transcriptionally downregulated by miR-199a. In summary, our findings revealed a novel role for Rab10 in pathogenic cardiac hypertrophy and suggest that Rab10 may be a potential therapeutic target for cardiac hypertrophic.

心脏肥厚延长是心力衰竭的主要危险因素。在心肌肥厚重塑过程中，蛋白质合成增加，蛋白质转运和定位到其功能位点。Rab gtpase是囊泡形成、运动和融合的关键调节因子，在这些过程中起着至关重要的作用。在这项研究中，我们发现Rab10，一个属于rabb家族的小GTPase，作为一种新的抑制心脏肥厚的调节剂。在初代新生大鼠心肌细胞（NRCMs）或小鼠模型中，angii或压力过载诱导心肌细胞肥大。我们发现，在肥厚应激后nrcm或小鼠心脏中Rab10的表达下调。Rab10过表达减轻心肌细胞肥厚，而其沉默加剧了表型，在体外证明了其重要的抗肥厚作用。为了确定Rab10在心脏中的体内作用，我们培育了心脏特异性Rab10过表达转基因小鼠（TG）。当接受Ang II输注或压力过载时，Rab10 TG小鼠表现出改善的收缩功能和减轻的肥厚重塑。相反，aav9介导的心脏特异性敲低Rab10显著加重了压力过载引起的心肌细胞肥大。机械上，Rab10抑制ERK1/2和AKT的磷酸化，从而减轻心肌肥厚的发生。此外，我们证明Rab10在转录后被miR-199a下调。总之，我们的研究结果揭示了Rab10在致病性心脏肥厚中的新作用，并提示Rab10可能是心脏肥厚的潜在治疗靶点。

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引用次数: 0

Deletion of CHOP in beta cell protects mice from cardiovascular complications in type 2 diabetes: evidence from a pre-clinical mouse model β细胞中CHOP的缺失可以保护2型糖尿病小鼠免受心血管并发症的影响：来自临床前小鼠模型的证据

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-10-22 DOI: 10.1016/j.jmccpl.2025.100492

Balaji Srinivas , Kiran Alluri , Nour-Eddine Rhaleb , Khalid Matrougui

Introduction

Cardiovascular complications are the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D), which is recognized as a major independent risk factor for coronary artery disease, stroke, peripheral vascular disease, and heart failure. The interrelationship between metabolic dysfunction and cardiovascular disease is complex and multifactorial, involving hyperglycemia, insulin resistance, inflammation, and oxidative stress. Evidence indicates that endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR) contribute to metabolic dysregulation and vascular dysfunction. However, the specific role of beta cell-derived UPR mediators, particularly C/EBP homologous protein (CHOP), in coordinating this interorgan axis between the endocrine pancreas and the cardiovascular system remains poorly understood.

Methods

To determine the role of beta cell CHOP in mediating the link between T2D and cardiovascular complications, we specifically deleted CHOP in beta cells. Thus, male and female β-cell^flox/flox and β-cell-specific CHOP knockout (β-cell^CHOP−/−) mice were fed a high-fat diet (HFD) or a control diet for four months. Metabolic, cardiovascular, and inflammatory parameters were assessed, including body weight, exercise capacity as measured by running distance, organ weights (heart, lung, pancreas, and kidney), glucose tolerance test (GTT), vascular endothelial function, cardiac fibrosis, and the expression of ER stress and inflammatory signaling markers.

Results

β-cell^flox/flox mice fed HFD for four months develop hallmark features of T2D, including obesity, glucose intolerance, impaired exercise capacity, cardiac fibrosis, vascular endothelial dysfunction, and increased organ weights. In contrast, β-cell^CHOP−/− mice are protected from these complications, demonstrating preserved glucose tolerance, endothelial function, reduced cardiac fibrosis, enhanced exercise performance, and blunted activation of ER stress and inflammatory pathways.

Conclusion

This study elucidates CHOP in pancreatic beta cells as a key mechanism linking T2D to cardiovascular complications. Deleting CHOP in beta cells reduces metabolic and cardiovascular issues, underscoring the role of beta cell stress in the connection between T2D and cardiovascular disease. These findings suggest that CHOP may be a potential target for preventing T2D-related cardiovascular complications.

心血管并发症是2型糖尿病（T2D）患者发病和死亡的主要原因，被认为是冠状动脉疾病、中风、外周血管疾病和心力衰竭的主要独立危险因素。代谢功能障碍与心血管疾病之间的相互关系是复杂和多因素的，涉及高血糖、胰岛素抵抗、炎症和氧化应激。有证据表明，内质网（ER）应激和未折叠蛋白反应（UPR）的诱导导致代谢失调和血管功能障碍。然而，β细胞衍生的UPR介质，特别是C/EBP同源蛋白（CHOP），在协调内分泌胰腺和心血管系统之间的器官间轴中的具体作用仍然知之甚少。方法为了确定β细胞CHOP在T2D和心血管并发症之间的介导作用，我们在β细胞中特异性地删除了CHOP。因此，雄性和雌性β-cellflox/flox和β-细胞特异性CHOP敲除（β-cellCHOP−/−）小鼠被喂食高脂肪饮食（HFD）或对照饮食四个月。评估代谢、心血管和炎症参数，包括体重、通过跑步距离测量的运动能力、器官重量（心、肺、胰腺和肾脏）、糖耐量试验（GTT）、血管内皮功能、心脏纤维化、内质网应激和炎症信号标志物的表达。结果β-cellflox/flox小鼠喂食HFD 4个月后出现T2D的标志性特征，包括肥胖、葡萄糖耐受不良、运动能力受损、心脏纤维化、血管内皮功能障碍和器官重量增加。相比之下，β-cellCHOP - / -小鼠免受这些并发症的影响，表现出葡萄糖耐量、内皮功能、心脏纤维化减少、运动表现增强、内质网应激和炎症途径的激活减弱。结论本研究阐明胰腺β细胞CHOP是t2dm与心血管并发症相关的关键机制。删除β细胞中的CHOP可减少代谢和心血管问题，强调β细胞应激在T2D和心血管疾病之间的关联中的作用。这些发现提示CHOP可能是预防t2d相关心血管并发症的潜在靶点。

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引用次数: 0

Age, sex, and vessel region affect the vasomotor function and gene expression signature of the aorta in mice 年龄、性别和血管区域影响小鼠主动脉血管舒缩功能和基因表达特征

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-10-19 DOI: 10.1016/j.jmccpl.2025.100491

Lars Saemann , Lotta Hartrumpf , Adrian-Iustin Georgevici , Sabine Pohl , Anne Großkopf , Kristin Wächter , Yuxing Guo , Andreas Simm , Gábor Szabó

Introduction

Vascular aging is associated with endothelial dysfunction, changes in vascular elasticity or stiffness, and the prevalence of cardiovascular diseases. Aging differs by sex. The effects of age, sex, and vessel region on arterial vasomotor function and gene expression signatures have not been explored yet. Thus, we investigated contraction, relaxation, and endothelial integrity, as well as gene expression, in the proximal and distal segments of the thoracic aorta in 6- and 18-month-old mice.

Materials and methods

Male and female C57BL/6J mice at 6 (n = 11/sex) and 18 (n = 12/sex) months of age were used. Segments of the proximal and distal thoracic aorta were mounted in organ bath chambers. We assessed the maximal receptor-independent contractility using potassium chloride (KCl), endothelial integrity using phenylephrine (PE), endothelial-dependent relaxation using acetylcholine (ACh), and endothelial-independent relaxation using sodium nitroprusside (SNP). Using microarrays, we performed transcriptomics on another 6 six mice of every subgroup.

Results

Endothelial integrity decreases significantly with age in male mice, but only in the proximal segment. The relaxation to ACh decreases with age in both sexes in the proximal and only in female individuals in the descending segment. In females, endothelial-dependent relaxation is higher than in males, in young age, independent of the segment, and in old age, still in the proximal segment. Endothelial-independent relaxation decreases with age only in the distal segment of female subjects. Genes associated with the electron transport chain, crucial for energy production in mitochondria, are decreased by age. The G-protein coupled receptor -G13 alpha subunit- signaling pathway and proteasome degradation, which are crucial for developing and maintaining endothelial integrity, were reduced in the aorta of old mice. Genes involved in endothelial nitric oxide synthesis were especially downregulated in old male mice.

Conclusion

Endothelial integrity and endothelial-dependent relaxation depend on age, sex, and segment of the descending thoracic aorta in mice. Genes associated with endothelial-dependent relaxation, endothelial integrity, and vascular aging change markedly by age, including some sex- and segment-specific differences.

血管老化与内皮功能障碍、血管弹性或硬度的改变以及心血管疾病的患病率有关。衰老因性别而异。年龄、性别和血管区域对动脉血管舒缩功能和基因表达特征的影响尚未探讨。因此，我们研究了6个月和18个月大的小鼠胸主动脉近端和远端段的收缩、松弛、内皮完整性以及基因表达。材料与方法选用6月龄（n = 11/sex）和18月龄（n = 12/sex）的C57BL/6J雄性和雌性小鼠。胸主动脉近段和远段分别安装在器官浴室中。我们使用氯化钾（KCl）评估了最大受体非依赖性收缩力，使用苯肾上腺素（PE）评估了内皮完整性，使用乙酰胆碱（ACh）评估了内皮依赖性松弛，使用硝普钠（SNP）评估了内皮非依赖性松弛。使用微阵列，我们对每个亚组的另外6只小鼠进行转录组学研究。结果随着年龄的增长，雄性小鼠内皮细胞的完整性明显下降，但仅在近端。在两性中，乙酰胆碱的弛豫在近端随着年龄的增长而减少，只有女性个体在下降段。在女性中，内皮依赖性松弛高于男性，在年轻时，独立于节段，在老年时，仍然在近端节段。内皮非依赖性松弛仅在女性受试者的远端节段随年龄而降低。与电子传递链相关的基因，对线粒体的能量产生至关重要，随着年龄的增长而减少。老龄小鼠主动脉中g蛋白偶联受体- g13 α亚基信号通路和蛋白酶体降解减少，这对内皮细胞的发育和维持完整性至关重要。参与内皮细胞一氧化氮合成的基因在老年雄性小鼠中尤其下调。结论小鼠胸降主动脉内皮完整性和内皮依赖性松弛与年龄、性别和节段有关。与内皮依赖性松弛、内皮完整性和血管老化相关的基因随着年龄的增长而发生显著变化，包括一些性别和节段特异性差异。

{"title":"Age, sex, and vessel region affect the vasomotor function and gene expression signature of the aorta in mice","authors":"Lars Saemann , Lotta Hartrumpf , Adrian-Iustin Georgevici , Sabine Pohl , Anne Großkopf , Kristin Wächter , Yuxing Guo , Andreas Simm , Gábor Szabó","doi":"10.1016/j.jmccpl.2025.100491","DOIUrl":"10.1016/j.jmccpl.2025.100491","url":null,"abstract":"<div><h3>Introduction</h3><div>Vascular aging is associated with endothelial dysfunction, changes in vascular elasticity or stiffness, and the prevalence of cardiovascular diseases. Aging differs by sex. The effects of age, sex, and vessel region on arterial vasomotor function and gene expression signatures have not been explored yet. Thus, we investigated contraction, relaxation, and endothelial integrity, as well as gene expression, in the proximal and distal segments of the thoracic aorta in 6- and 18-month-old mice.</div></div><div><h3>Materials and methods</h3><div>Male and female C57BL/6J mice at 6 (<em>n</em> = 11/sex) and 18 (<em>n</em> = 12/sex) months of age were used. Segments of the proximal and distal thoracic aorta were mounted in organ bath chambers. We assessed the maximal receptor-independent contractility using potassium chloride (KCl), endothelial integrity using phenylephrine (PE), endothelial-dependent relaxation using acetylcholine (ACh), and endothelial-independent relaxation using sodium nitroprusside (SNP). Using microarrays, we performed transcriptomics on another 6 six mice of every subgroup.</div></div><div><h3>Results</h3><div>Endothelial integrity decreases significantly with age in male mice, but only in the proximal segment. The relaxation to ACh decreases with age in both sexes in the proximal and only in female individuals in the descending segment. In females, endothelial-dependent relaxation is higher than in males, in young age, independent of the segment, and in old age, still in the proximal segment. Endothelial-independent relaxation decreases with age only in the distal segment of female subjects. Genes associated with the electron transport chain, crucial for energy production in mitochondria, are decreased by age. The G-protein coupled receptor -G13 alpha subunit- signaling pathway and proteasome degradation, which are crucial for developing and maintaining endothelial integrity, were reduced in the aorta of old mice. Genes involved in endothelial nitric oxide synthesis were especially downregulated in old male mice.</div></div><div><h3>Conclusion</h3><div>Endothelial integrity and endothelial-dependent relaxation depend on age, sex, and segment of the descending thoracic aorta in mice. Genes associated with endothelial-dependent relaxation, endothelial integrity, and vascular aging change markedly by age, including some sex- and segment-specific differences.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100491"},"PeriodicalIF":2.2,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac magnetic resonance imaging and cardiac scintigraphy in the diagnosis of cardiac amyloidosis: A meta-analysis of 4866 patients 心脏磁共振成像和心脏闪烁成像诊断心脏淀粉样变性：4866例患者的荟萃分析

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-10-17 DOI: 10.1016/j.jmccpl.2025.100489

Mahmoud Balata , Abdelrahman M.Attia , Mohamed Ibrahim Gbreel , Mamdouh Elsmaan , Marwa Hassan , Paul Rapeanu , Milka Marinova , Marc Ulrich Becher , Islam Ebeid , Jasmin Ortak , Hüseyin Ince

Introduction

Cardiac amyloidosis (CA) impacts about 20 % of elderly heart failure patients, leading to myocardial dysfunction and life-threatening risks. However, it often remains undetected due to the significant risks associated with invasive biopsies. This highlights the critical need for safer and accurate non-invasive diagnostic techniques.

Aim

To compare the diagnostic value of Cardiac Magnetic Resonance (CMR) imaging and Cardiac Scintigraphy Imaging in the diagnosis of CA.

Methods

A comprehensive literature search across PubMed, Scopus, Web of Science, and Cochrane databases yielded studies that utilized CMR or cardiac scintigraphy for diagnosing CA. QUADAS-2 was employed for quality assessment.

Results

From 7117 records, 35 studies involving 4866 patients were analyzed. Cardiac scintigraphy demonstrated higher sensitivity and specificity across different radiotracers, with 99mTc-HMDP showing the highest specificity (1.00, 95 % CI: 0.93–1.00) and 99mTc-DPD the highest sensitivity (0.93, 95 % CI: 0.89–0.95). CMR imaging showed variable diagnostic accuracy with a sensitivity of 0.83 (95 % CI: 0.81–0.85) and a lower specificity of only 0.53 (95 % CI: 0.50–0.56).

Conclusion

Cardiac scintigraphy, particularly with 99mTc-HMDP, offers superior diagnostic accuracy for CA compared to CMR imaging. Controlled, randomized, prospective studies directly comparing these non-invasive techniques are essential to validate these findings.

心脏淀粉样变性（CA）影响约20%的老年心力衰竭患者，导致心肌功能障碍和危及生命的风险。然而，由于与侵入性活检相关的重大风险，它往往未被发现。这凸显了对更安全、准确的非侵入性诊断技术的迫切需求。目的比较心脏磁共振（CMR）和心脏显像（Scintigraphy）对CA的诊断价值。方法通过PubMed、Scopus、Web of Science和Cochrane数据库的综合文献检索，获得利用CMR或Scintigraphy诊断CA的研究，并采用QUADAS-2进行质量评价。结果从7117份记录中，分析了35项研究，涉及4866例患者。心脏闪烁成像在不同的放射性示踪剂中表现出更高的敏感性和特异性，99mTc-HMDP具有最高的特异性（1.00,95% CI: 0.93 - 1.00）， 99mTc-DPD具有最高的敏感性（0.93,95% CI: 0.89-0.95）。CMR成像显示出可变的诊断准确性，敏感性为0.83 (95% CI: 0.81-0.85)，特异性较低，仅为0.53 （95% CI: 0.50-0.56）。结论与CMR相比，心脏显像，特别是99mTc-HMDP对CA的诊断准确性更高。直接比较这些非侵入性技术的对照、随机、前瞻性研究对于验证这些发现至关重要。

{"title":"Cardiac magnetic resonance imaging and cardiac scintigraphy in the diagnosis of cardiac amyloidosis: A meta-analysis of 4866 patients","authors":"Mahmoud Balata , Abdelrahman M.Attia , Mohamed Ibrahim Gbreel , Mamdouh Elsmaan , Marwa Hassan , Paul Rapeanu , Milka Marinova , Marc Ulrich Becher , Islam Ebeid , Jasmin Ortak , Hüseyin Ince","doi":"10.1016/j.jmccpl.2025.100489","DOIUrl":"10.1016/j.jmccpl.2025.100489","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiac amyloidosis (CA) impacts about 20 % of elderly heart failure patients, leading to myocardial dysfunction and life-threatening risks. However, it often remains undetected due to the significant risks associated with invasive biopsies. This highlights the critical need for safer and accurate non-invasive diagnostic techniques.</div></div><div><h3>Aim</h3><div>To compare the diagnostic value of Cardiac Magnetic Resonance (CMR) imaging and Cardiac Scintigraphy Imaging in the diagnosis of CA.</div></div><div><h3>Methods</h3><div>A comprehensive literature search across PubMed, Scopus, Web of Science, and Cochrane databases yielded studies that utilized CMR or cardiac scintigraphy for diagnosing CA. QUADAS-2 was employed for quality assessment.</div></div><div><h3>Results</h3><div>From 7117 records, 35 studies involving 4866 patients were analyzed. Cardiac scintigraphy demonstrated higher sensitivity and specificity across different radiotracers, with 99mTc-HMDP showing the highest specificity (1.00, 95 % CI: 0.93–1.00) and 99mTc-DPD the highest sensitivity (0.93, 95 % CI: 0.89–0.95). CMR imaging showed variable diagnostic accuracy with a sensitivity of 0.83 (95 % CI: 0.81–0.85) and a lower specificity of only 0.53 (95 % CI: 0.50–0.56).</div></div><div><h3>Conclusion</h3><div>Cardiac scintigraphy, particularly with 99mTc-HMDP, offers superior diagnostic accuracy for CA compared to CMR imaging. Controlled, randomized, prospective studies directly comparing these non-invasive techniques are essential to validate these findings.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100489"},"PeriodicalIF":2.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nanoscale architecture and dynamics of CaV1.3 channel clusters in cardiac myocytes revealed by single channel nanoscopy 单通道纳米显微镜显示心肌细胞CaV1.3通道簇的纳米结构和动力学

IF 2.2

Journal of molecular and cellular cardiology plus

Pub Date : 2025-10-16 DOI: 10.1016/j.jmccpl.2025.100490

Niko Schwenzer , Roman Tsukanov , Tobias Kohl , Samrat Basak , Izzatullo Sobitov , Fitzwilliam Seibertz , Rohan Kapoor , Niels Voigt , Jörg Enderlein , Stephan E. Lehnart

The clustering of L-type calcium channels (LTCC) for functional regulation of intracellular calcium signaling remains poorly understood. Here we applied super-resolution imaging to study Ca_V1.3 channel clusters in human iPSC-derived atrial cardiomyocytes (hiPSC-aCM) to analyze subcellular localization, dimensions, architecture, and dynamics, which were largely unexplored previously. STimulated Emission Depletion (STED) imaging characterized the localization and structure of Ca_V1.3 channel clusters in living cardiomyocytes. DNA Points Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) achieved true molecular resolution, revealing an irregular channel distribution with substantial spacing. Single Particle Tracking (SPT) showed that channels co-diffuse in confined and stationary membrane nanodomains. The cytosolic C-terminal tail of Ca_V1.3 by itself was found sufficient for cluster formation. In conclusion, our LTCC clustering studies demonstrate that Ca_V1.3 channel clusters consist of mobile individual channels inside defined membrane nanodomains, in contrast to previous models of dense channel packing.

l型钙通道（LTCC）的聚类对细胞内钙信号的功能调节仍知之甚少。在这里，我们应用超分辨率成像技术研究了人类ipsc来源的心房心肌细胞（hiPSC-aCM）中的CaV1.3通道簇，以分析亚细胞定位、尺寸、结构和动力学，这在很大程度上是以前未被探索的。受激辐射损耗（STED）成像表征了活心肌细胞中CaV1.3通道簇的定位和结构。DNA点积累成像技术（DNA- paint）实现了真正的分子分辨率，揭示了具有大量间距的不规则通道分布。单粒子跟踪（SPT）表明通道在受限和固定的膜纳米畴中共扩散。发现CaV1.3的胞质c端尾本身足以形成簇。总之，我们的LTCC聚类研究表明，与之前的密集通道填充模型相比，CaV1.3通道簇由定义膜纳米域内的移动单个通道组成。

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引用次数: 0