Cell calcium最新文献_第5页

GAT3-dependent regulation of glioma invasiveness via a lipid raft-associated PMCA4 Ca2+ transporter and a downstream CaMKII/CREB signaling – implications for compartmentalized signaling in glioma tumors 通过脂质筏相关的PMCA4 Ca2+转运体和下游CaMKII/CREB信号传导对胶质瘤侵袭性的gat3依赖性调节-对胶质瘤肿瘤区隔化信号传导的影响

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-06-19 DOI: 10.1016/j.ceca.2025.103050

Marta Sobolczyk-Prawda , Agnieszka Kapsa , Malwina Lisek , Julia Tomczak , Katarzyna Sobierajska , Maciej Radek , Feng Guo , Tomasz Boczek

Emerging evidence underscores the crucial role of compartmentalized Ca²⁺ and GABA signaling in the development and progression of gliomas. Our findings reveal that low GAT3 expression and high PMCA4 levels are strongly associated with poor survival outcomes in glioma patients, suggesting their involvement in tumor progression. Using C6 glioma model, we uncovered a dynamic interaction between GAT3 and PMCA4 within lipid raft microdomains, which plays a key role in fine-tuning of localized Ca²⁺ dynamics in response to GABA stimulation. Knockdown of PMCA4 increased resting Ca²⁺concentration and enhanced Ca²⁺ accumulation in lipid rafts following 3-min pulse GABA stimulation, significantly impairing glioma cell migration and invasion. Interestingly, the expression of Ca²⁺ chelator parvalbumin in rafts abolished both baseline and GABA-stimulated Ca²⁺ rises, effectively restoring the migratory and invasive potential of tumor cells. We further demonstrated that GAT3 interacted with calmodulin, a pivotal regulator of PMCA4, and this interaction was decreased following 24 h GABA treatment. Long-term GABA stimulation also disrupted PMCA4/GAT3 complex, overloaded lipid rafts with Ca²⁺ and decreased glioma invasiveness in the presence of PMCA4. In these conditions, we observed GAT3- and Ca²⁺/calmodulin-dependent protein kinase II-dependent CREB phosphorylation at Ser133, which was controlled by Ca²⁺ events in lipid rafts and required to maintain glioma invasiveness. Our study uncovers a previously unrecognized GAT3-dependent mechanism of Ca²⁺compartmentalization in membrane microdomains, shedding new light on its potential role in tumor behavior. Understanding these local Ca²⁺ signaling partnerships will offer valuable insights into gliomagenesis and could lead to the development of novel therapeutic strategies for glioma treatment.

新出现的证据强调了区隔化Ca 2 +和GABA信号在胶质瘤发生和发展中的关键作用。我们的研究结果表明，低GAT3表达和高PMCA4水平与胶质瘤患者的不良生存结果密切相关，表明它们参与肿瘤进展。利用C6胶质瘤模型，我们发现了脂筏微域内GAT3和PMCA4之间的动态相互作用，这在GABA刺激下局部Ca2+动力学的微调中起关键作用。在3分钟脉冲GABA刺激后，PMCA4的下调增加了静息Ca2+浓度，增强了脂筏中Ca2+的积累，显著损害了胶质瘤细胞的迁移和侵袭。有趣的是，筏中Ca2+螯合剂小白蛋白的表达消除了基线和gaba刺激的Ca2+升高，有效地恢复了肿瘤细胞的迁移和侵袭潜力。我们进一步证明GAT3与钙调蛋白相互作用，钙调蛋白是PMCA4的关键调节因子，并且这种相互作用在24小时的GABA处理后减少。长期GABA刺激也会破坏PMCA4/GAT3复合物，超载Ca2+脂筏，并降低PMCA4存在时胶质瘤的侵袭性。在这些条件下，我们观察到GAT3-和Ca2+/钙调素依赖性蛋白激酶ii依赖性CREB的Ser133磷酸化，这是由脂筏中的Ca2+事件控制的，是维持胶质瘤侵袭性所必需的。我们的研究揭示了一种以前未被认识的膜微域中Ca2+区隔化的gat3依赖机制，为其在肿瘤行为中的潜在作用提供了新的视角。了解这些局部Ca 2 +信号伙伴关系将为胶质瘤发生提供有价值的见解，并可能导致胶质瘤治疗新治疗策略的开发。

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引用次数: 0

Calcium at the crossroads: TPC2’s role in LRRK2-linked Parkinson’s disease 十字路口的钙：TPC2在lrrk2相关帕金森病中的作用

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-06-17 DOI: 10.1016/j.ceca.2025.103049

Federica De Lazzari , Simone Wanderoy , Alexander J Whitworth

The pathogenic mechanisms of LRRK2 are hotly debated but regulation of lysosomal homeostasis has emerged as a leading focus area. In recent work, Gregori et al. show that Ca²⁺ release through the lysosomal Two-Pore Channel 2 (TPC2) could be a significant contributor to dopaminergic neuron vulnerability.

LRRK2的致病机制一直备受争议，但对溶酶体稳态的调节已成为一个主要的焦点领域。在最近的工作中，Gregori等人表明，通过溶酶体双孔通道2 （TPC2）释放Ca2+可能是多巴胺能神经元易感性的一个重要因素。

引用次数: 0

Paclitaxel activates SOCE/ICRAC in dorsal root ganglion neurons: implications for paclitaxel-induced peripheral neuropathy 紫杉醇激活背根神经节神经元的SOCE/ICRAC：紫杉醇诱导的周围神经病变的意义

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-05-27 DOI: 10.1016/j.ceca.2025.103040

Marta Delconti , Tiziana Ravasenga , Marianna Dionisi , Tiziana Romanazzi , Fausto Chiazza , Silvia Giatti , Dmitry Lim , Armando A. Genazzani , Beatrice Riva , Cristina Meregalli , Guido Cavaletti , Carla Distasi

Paclitaxel (PTX) is one of the most widely used antineoplastic drugs for the treatment of solid cancers. Its mechanism of action involves binding to β-tubulin subunits, leading to the stabilization of microtubule polymers and subsequent cell cycle arrest. Despite its efficacy, PTX is associated with significant adverse effects, most notably peripheral neurotoxicity and neuropathic pain, which represent the primary dose-limiting side effects. In sensory neurons, PTX affects multiple molecular pathways, with early alterations in excitability and calcium signaling following acute drug exposure. To investigate these mechanisms, we employed a combination of calcium imaging, electrophysiological techniques, and pharmacological approaches to explore the role of ORAI channels in the excitability and calcium dynamics of mouse dorsal root ganglion neurons. Our findings reveal that acute exposure to low doses of PTX triggers IP₃-dependent calcium release and activates a store-operated calcium entry through STIM-ORAI dependent I_CRAC. Moreover, acute PTX application induced the activation of a sustained calcium inward current, V_m depolarization and triggered action potential firing that was strongly attenuated by I_CRAC inhibition. Molecular analyses further revealed a significant upregulation of Orai1, Orai2, and Stim2 mRNA levels, accompanied by elevated ORAI1 protein expression, in a rat model of paclitaxel-induced peripheral neuropathy. These results suggest that ORAI and STIM proteins represent promising molecular targets for developing therapies aimed at mitigating the side effects of PTX.

紫杉醇（Paclitaxel， PTX）是目前应用最广泛的治疗实体肿瘤的抗肿瘤药物之一。其作用机制包括与β-微管蛋白亚基结合，导致微管聚合物的稳定和随后的细胞周期阻滞。尽管其疗效良好，但PTX也有明显的不良反应，最明显的是周围神经毒性和神经性疼痛，这是主要的剂量限制性副作用。在感觉神经元中，PTX影响多种分子通路，在急性药物暴露后早期改变兴奋性和钙信号。为了研究这些机制，我们采用钙成像、电生理技术和药理学方法相结合的方法来探索ORAI通道在小鼠背根神经节神经元的兴奋性和钙动力学中的作用。我们的研究结果表明，急性暴露于低剂量的PTX会触发ip3依赖性钙释放，并通过STIM-ORAI依赖性ICRAC激活储存操作的钙进入。此外，急性PTX应用诱导持续钙向内电流的激活，Vm去极化和触发动作电位放电，这被ICRAC抑制强烈减弱。分子分析进一步显示，在紫杉醇诱导的大鼠周围神经病变模型中，Orai1、Orai2和Stim2 mRNA水平显著上调，同时Orai1蛋白表达升高。这些结果表明，ORAI和STIM蛋白是开发旨在减轻PTX副作用的治疗方法的有希望的分子靶点。

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引用次数: 0

Campari2 genomic interrogation of homeostatic calcium activity identifies TIM1 as a negative regulator of T cell function Campari2基因组对稳态钙活性的研究表明TIM1是T细胞功能的负调节因子

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-05-17 DOI: 10.1016/j.ceca.2025.103036

Sana Kouba , Xin Zhang , Raphael Néré, Cyril Castelbou, Nicolas Demaurex, Amado Carreras-Sureda

Calcium signals regulate crucial cellular functions yet many genes coding for Ca²⁺handling proteins remain unknown as their identification relies on low-throughput single-cell approaches. Here we describe a method to measure Ca²⁺ activity using CaMPARI2, flow cytometry and pooled genome interrogation. CAMPARI2 screen (CaMP-Screen) identified enhancers and inhibitors of homeostatic Ca²⁺ activity, highlighting a predominant role for store-operated Ca²⁺ entry (SOCE) and lipid signalling pathways. Genes reducing basal Ca²⁺ activity were linked to Prader Willy syndrome, T cell dysfunction, and deafness. Silencing of HAVCR1 gene, coding for T cell transmembrane immunoglobulin and mucin (TIM1), enhanced Ca²⁺ signals in T cells and promoted signaling under resting but not after TCR engagement. Our findings establish CaMP-Screen as an efficient detector of low-amplitude Ca²⁺ signals and identify new genes associated to pathologies that regulate Ca²⁺ homeostasis, reporting TIM1 as a negative regulator of Ca²⁺ signals driving T cell function.

钙信号调节关键的细胞功能，但许多编码Ca2+处理蛋白的基因仍然未知，因为它们的鉴定依赖于低通量的单细胞方法。在这里，我们描述了一种使用CaMPARI2，流式细胞术和汇集基因组询问来测量Ca2+活性的方法。CAMPARI2筛选（CaMP-Screen）鉴定了稳态Ca2+活性的增强子和抑制剂，突出了存储操作的Ca2+进入（SOCE）和脂质信号通路的主要作用。降低基础Ca2+活性的基因与Prader Willy综合征、T细胞功能障碍和耳聋有关。沉默编码T细胞跨膜免疫球蛋白和粘蛋白（TIM1）的HAVCR1基因，可以增强T细胞中的Ca2+信号，并在静止状态下促进信号传导，而在TCR参与后则没有。我们的研究结果建立了CaMP-Screen作为低振幅Ca2+信号的有效检测器，并鉴定了与调节Ca2+稳态的病理相关的新基因，报告TIM1是驱动T细胞功能的Ca2+信号的负调节因子。

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引用次数: 0

The role of SERCA in vascular diseases, a potential therapeutic target SERCA在血管疾病中的作用，一个潜在的治疗靶点

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-05-07 DOI: 10.1016/j.ceca.2025.103039

Qinghua Yu, Wen Tian

SERCA, the sarco/endoplasmic reticulum Ca²⁺-ATPase, is a pivotal protein that transports calcium ions (Ca²⁺) from the cytoplasm into the sarcoplasmic/endoplasmic reticulum (SR/ER), thus sustaining cellular Ca²⁺ homeostasis. A growing body of evidence indicates that SERCA dysfunction correlates with disrupted cellular Ca²⁺ homeostasis and ER stress, precipitating a spectrum of chronic diseases. As a regulator of Ca²⁺ homeostasis, SERCA emerges as a potential therapeutic target for conditions associated with Ca²⁺ imbalance. This review delineates the association between SERCA and a variety of vascular diseases.

sarca，即肌浆/内质网Ca2+- atp酶，是将钙离子（Ca2+）从细胞质转运到肌浆/内质网（SR/ER），从而维持细胞Ca2+稳态的关键蛋白。越来越多的证据表明，SERCA功能障碍与细胞Ca2+稳态破坏和内质网应激相关，从而引发一系列慢性疾病。作为Ca2+稳态的调节因子，SERCA成为Ca2+失衡相关疾病的潜在治疗靶点。本文综述了SERCA与多种血管疾病之间的关系。

引用次数: 0

Stable expression of SARS-CoV-2 envelope viroporin promotes intracellular calcium depletion in human cells: relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation SARS-CoV-2包膜病毒孔蛋白的稳定表达促进人细胞内钙的消耗：与内质网应激、细胞增殖、多能性和谱系分化的相关性

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-04-18 DOI: 10.1016/j.ceca.2025.103032

Cesare Sala , Andrea Ninu , Valentina Balducci , Giada Allegro , Alberto Montalbano , Matteo Lulli , Martina Lucia Boccitto , Elena Guzzolino , Valentina Spinelli , Annarosa Arcangeli , Laura Sartiani , Elisabetta Cerbai

SARS-CoV-2 infection affects the respiratory system but also many tissues and organs that may be adversely compromised. Accordingly, recent evidence has assessed virus ability to infect different cell phenotypes, translate viral proteins and promote virus replication. Among them, Envelope (E) proteins sustain virus replication, promote inflammatory processes and remodelling of host cells. However, despite advances on structure and sequence, E-protein specific location and effects in human host cells are still controversial and poorly investigated.

Using lentiviral vectors, we established HEK293 and hiPS cell lines stably expressing E-protein. Immunocytochemistry showed E-protein mainly locates within the endoplasmic reticulum, the ERGIC and the Golgi compartments, while only HEK293 cells display some protein staining in cell periphery suggesting a possible insertion into the plasmalemma. Electrophysiological recordings in HEK293 cells revealed E-protein self-assembles in the plasma membrane to mediate a cation efflux pore that is sensitive to amantadine blockade. Calcium fluorescence imaging in HEK293 and hiPS cells demonstrated E-protein expression induces a marked depletion of thapsigargin-sensitive intracellular calcium stores. The altered calcium homeostasis associates to reduced cell metabolic activity, mitochondrial potential, proliferation rate and promotes ER stress. Finally, trilineage differentiation of hiPS cells indicated E-protein expression preserves cell pluripotency while selectively impairs mesodermal differentiation. These results unveil a critical role of stable E-viroporin expression that through alteration of ER Ca²⁺ homeostasis, metabolic activity and induction of ER stress affects important cellular functions, including the differentiative process from pluripotent to mesodermal progenitors, a critical cell population in self-repair and homeostasis of most human tissue and organs.

SARS-CoV-2感染会影响呼吸系统，但也会影响许多可能受到不利损害的组织和器官。因此，最近的证据评估了病毒感染不同细胞表型、翻译病毒蛋白和促进病毒复制的能力。其中，包膜(E)蛋白维持病毒复制，促进炎症过程和宿主细胞的重塑。然而，尽管在结构和序列方面取得了进展，但e蛋白在人宿主细胞中的特异性定位和作用仍然存在争议，研究也很少。利用慢病毒载体，建立了稳定表达e蛋白的HEK293和hiPS细胞系。免疫细胞化学显示e蛋白主要位于内质网、ERGIC和高尔基区室内，而HEK293细胞仅在细胞外周显示一些蛋白染色，提示可能插入质膜。HEK293细胞的电生理记录显示，e蛋白在质膜中自组装，介导对金刚烷胺阻断敏感的阳离子外排孔。HEK293和hiPS细胞的钙荧光成像显示，e蛋白的表达导致细胞内对thapsigargin敏感的钙储存明显减少。钙稳态的改变与细胞代谢活性、线粒体电位、增殖率降低有关，并促进内质网应激。最后，hiPS细胞的三龄分化表明，e蛋白的表达保留了细胞的多能性，但选择性地损害了中胚层分化。这些结果揭示了稳定的E-viroporin表达的关键作用，通过改变ER Ca 2 +的稳态、代谢活性和诱导ER应激影响重要的细胞功能，包括从多能祖细胞到中胚层祖细胞的分化过程，这是大多数人体组织和器官自我修复和稳态的关键细胞群。

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引用次数: 0

The role of ion channels in the regulation of dendritic cell function 离子通道在树突状细胞功能调控中的作用

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-04-16 DOI: 10.1016/j.ceca.2025.103031

Shi-Li Zhou , Lan-Lan Zhong , Yi-Lan Wu , Si-Wen Ji , Yong Li , Na Niu

Ion channels, membrane proteins that facilitate the transport of various inorganic ions across hydrophobic cellular lipid membranes, are ubiquitous in a wide variety of cell and tissue types. They are involved in establishing the cell membrane potential and play a role in various physiological activities by regulating ion concentrations within the cell. Dendritic cells (DCs) are specialised antigen-presenting cells found mainly on the surface of the body (skin and mucous membranes), in the mesenchyme of most organs, in the T-cell compartment of the spleen and in lymph nodes. DCs exert an important influence on the regulation of inflammation by activating T cells and producing cytokines. Studies have shown that ion channels expressed in DCs contribute to the regulation of the immune response, making them a key component of the immune system. This review summarises the major scientific advances in understanding the functional impact of ion channels (calcium channels, sodium channels and aquaporin) in DCs, including the regulation of inflammatory responses, antigen presentation, maturation, migration and cytokine production, to inform ongoing studies of ion channel function in DCs.

离子通道是促进各种无机离子通过疏水细胞脂质膜运输的膜蛋白，在各种细胞和组织类型中普遍存在。它们参与细胞膜电位的建立，并通过调节细胞内离子浓度在各种生理活动中发挥作用。树突状细胞（dc）是一种特殊的抗原呈递细胞，主要存在于身体表面（皮肤和粘膜）、大多数器官的间质、脾脏的t细胞区和淋巴结中。dc通过激活T细胞和产生细胞因子对炎症的调节发挥重要影响。研究表明，dc中表达的离子通道有助于调节免疫反应，使其成为免疫系统的关键组成部分。本文综述了离子通道（钙通道、钠通道和水通道蛋白）在树突细胞中功能影响的主要科学进展，包括炎症反应、抗原呈递、成熟、迁移和细胞因子产生的调节，为正在进行的树突细胞中离子通道功能的研究提供信息。

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引用次数: 0

Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling 钙作为线粒体-核网络驱动的逆行信号的关键决定因素

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-04-08 DOI: 10.1016/j.ceca.2025.103017

Kriti Ahuja, Rajender K. Motiani

Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca²⁺), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca²⁺signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca²⁺uptake through silencing of Mitochondrial Ca²⁺Uniporter (MCU) leads to Ca²⁺oscillations in the cytosol. The rise in cytosolic Ca²⁺ results in activation of Ca²⁺ sensitive transcription factors such as NFATs and NF-

κ

B. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca²⁺ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.

线粒体是调节多种细胞功能的强大信号细胞器。驱动线粒体信号传导的关键机制之一是细胞器间串扰。线粒体主要通过钙（Ca2+）、活性氧（ROS）和脂质在细胞器膜上的交换与其他细胞器进行通信。线粒体有自己的基因组，但大部分线粒体蛋白是由核基因组编码的。因此，线粒体的一些功能是由细胞核通过顺行信号控制的。然而，线粒体在驱动核基因组编码基因表达中的作用近年来引起了人们的关注。最近的独立研究小组已经证明了线粒体Ca2+信号在刺激核基因表达中的关键作用。这些研究报道了通过沉默线粒体Ca2+单转运蛋白（MCU）抑制线粒体Ca2+摄取导致细胞质中Ca2+振荡。胞浆内Ca2+的升高导致Ca2+敏感转录因子如nfat和NF-κB的激活。这些转录因子因此诱导其靶基因在核基因组中的表达。重要的是要强调，这些小组使用不同的细胞类型，并优雅地呈现了一种在不同系统中保守的现象。值得注意的是，线粒体Ca2+信号介导的转录调节控制着多种细胞功能，包括b细胞活化、黑色素生成和衰老相关炎症。未来对这一信号模块的研究将有助于更好地理解人类病理生理学中的这一轴，并可能导致新的治疗策略的发展。

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引用次数: 0

Scaling up neuronal Ca2+, signaling on ER ladders 放大神经元Ca2+，内质网梯子上的信号

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-04-01 DOI: 10.1016/j.ceca.2025.103016

Khaled Machaca

Dendritic Ca²⁺ signaling is critical for neural transmission and signal processing, however the detailed molecular mechanisms have not been elucidated. Using elegant and complementary imaging approaches Benedetti et al. discover a distinctive ER ladder architecture in dendrites and show that precise localization of Ca²⁺ signaling proteins at endoplasmic reticulum (ER)-plasma membrane (PM) junctions supports integration of Ca²⁺ signaling along the dendrite.

树突Ca2+信号是神经传递和信号处理的关键，但详细的分子机制尚未阐明。Benedetti等人使用优雅和互补的成像方法发现树突中独特的内质网阶梯结构，并表明Ca2+信号蛋白在内质网(ER)-质膜（PM）连接处的精确定位支持Ca2+信号沿树突的整合。

引用次数: 0

H2S treatment reverts cardiac hypertrophy and increases SERCA2a activity but does not fully restore cardiac Ca2+ handling in hypertensive rats 在高血压大鼠中，H2S处理可恢复心脏肥厚并增加SERCA2a活性，但不能完全恢复心脏Ca2+处理

IF 4.3 2区生物学 Q2 CELL BIOLOGY

Cell calcium

Pub Date : 2025-03-25 DOI: 10.1016/j.ceca.2025.103015

Grecia J. Medina-Terol , Luis Chimal , Saúl Huerta de la Cruz , Guillermo Ávila , Alberto Aranda , David Cruz-Robles , David Centurión , Julio Altamirano , Rocio Rojo , Norma Leticia Gómez-Viquez

Hydrogen sulfide (H₂S) has been proposed to play a cardioprotective role, particularly due to its ability to revert left ventricular hypertrophy (LVH) and mitigate cardiac dysfunction in various cardiomyopathies, including hypertensive heart disease. However, the extent to which cardioprotection by H₂S involves improvement in Ca²⁺ handling remains unclear. Although H₂S has been reported to influence the function of key Ca²⁺ handling proteins, most studies have focused on acute administration of H₂S donors in isolated cardiomyocytes, rather than in a therapeutic context. In this study, we used a rat model of hypertension induced by abdominal aortic coarctation (AAC) to evaluate the therapeutic potential of NaHS, an H₂S donor, on LVH and Ca²⁺ handling. After 8 weeks of AAC, hypertensive rats developed moderate LVH, which was accompanied by a reduction in both the amplitude and the rate of rise of systolic Ca²⁺ transients, as well as a decrease in sarcoplasmic reticulum (SR) Ca²⁺ load. Despite the reduced SR Ca²⁺ load, the frequency of diastolic Ca²⁺ sparks remained high, while the incidence and propagation rate of spontaneous Ca²⁺ waves significantly increased, suggesting enhanced diastolic SR Ca²⁺ leak, most likely due to hypersensitivity of ryanodine receptors (RyR2) to Ca²⁺. On the other hand, NaHS administration during the final 4 weeks of AAC reverted both LVH and hypertension, and increased SR Ca²⁺ reuptake mediated by the SR Ca²⁺ ATPase (SERCA2a). However, NaHS treatment failed to restore the amplitude and rate of rise of systolic Ca²⁺ transients or SR Ca²⁺ load. Furthermore, SR Ca²⁺ leak might have worsened, since spontaneous Ca²⁺ waves increased. In conclusion, NaHS treatment does not appear to normalize all Ca²⁺ handling properties during hypertensive LVH. On the contrary, NaHS may exert an arrhythmogenic effect, likely due to enhanced SERCA2a activity under conditions of unresolved RyR2 Ca²⁺ hypersensitivity.

硫化氢（H2S）已被提出发挥心脏保护作用，特别是由于它能够恢复左心室肥厚（LVH）和减轻各种心肌病（包括高血压心脏病）的心功能障碍。然而，H2S的心脏保护在多大程度上涉及Ca2+处理的改善仍不清楚。尽管有报道称H2S会影响关键Ca2+处理蛋白的功能，但大多数研究都集中在分离心肌细胞中急性给予H2S供体，而不是在治疗背景下。在这项研究中，我们使用腹主动脉缩窄（AAC）引起的高血压大鼠模型来评估H2S供体NaHS对LVH和Ca2+处理的治疗潜力。AAC治疗8周后，高血压大鼠出现中度LVH，伴有收缩Ca2+瞬态的幅度和上升速率降低，肌浆网（SR） Ca2+负荷降低。尽管降低了SR Ca2+负荷，舒张期Ca2+火花的频率仍然很高，而自发Ca2+波的发生率和传播率显著增加，表明舒张期SR Ca2+泄漏增强，很可能是由于ryanodine受体（RyR2）对Ca2+的超敏反应。另一方面，在AAC的最后4周给予NaHS可以恢复LVH和高血压，并增加SR Ca2+ atp酶（SERCA2a）介导的SR Ca2+再摄取。然而，NaHS治疗未能恢复收缩期Ca2+瞬态或SR Ca2+负荷的幅度和上升速度。此外，由于自发Ca2+波增加，SR Ca2+泄漏可能恶化。总之，NaHS治疗似乎并没有使高血压LVH期间的所有Ca2+处理特性正常化。相反，NaHS可能发挥致心律失常的作用，可能是由于在未解决的RyR2 Ca2+超敏状态下SERCA2a活性增强。

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引用次数: 0