Journal of molecular and cellular cardiology最新文献

英文中文

JTC801 inhibited CA9 activation via HIF-1α to promotes alkaliptosis in vascular smooth muscle cells and alleviate the formation of aortic dissection JTC801通过HIF-1α抑制CA9活化，促进血管平滑肌细胞碱沉，减轻主动脉夹层的形成。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-19 DOI: 10.1016/j.yjmcc.2025.12.005

Yang Zhou , Xiao-Ping Xie , Bo-Lai Shen , Ao Wang , Bo-Wen Li , Zhi-Wei Wang

Background

Aortic dissection (AD) is a life-threatening cardiovascular condition characterized by high morbidity and mortality rates. However, the molecular mechanism of intracellular pH in AD development has not been fully elucidated. In this study, the role of carbonic anhydrase 9 (CA9) in VSMCs intracellular pH and the regulatory mechanism were investigated.

Methods

Cell viability was examined by cell counting kit-8 (CCK-8) and intracellular pH was detected by BCECF-AM probe. The regulation of CA9 transcription by HIF-1α was measured by Cut &run-qPCR assay. The levels of CA9, HIF-1α, MMP2 and α-SMA were evaluated by RT-qPCR, Western blot and Immunofluorescence.

Results

Our results demonstrated that CA9 was significantly upregulated in AD tissues, primarily localized in VSMCs, and associated with increased MMP2 levels, while α-SMA levels decreased. Silencing CA9 in VSMCs resulted in reduced cell viability and increased intracellular pH. Additionally, we found that HIF-1α was upregulated in AD, regulating CA9 expression in VSMCs. Treatment with JTC801 in a BAPN-induced mouse model reduced CA9 and HIF-1α expression, improving survival and decreasing AD incidence.

Conclusion

This study establishes CA9 as a hypoxia-responsive mediator of pH dysregulation in AD, modulated by HIF-1α. Targeting the HIF-1α/CA9 axis with JTC801 presents a novel therapeutic strategy to restore VSMC homeostasis and ECM integrity. These findings advance our understanding of intracellular pH in AD and highlight this approach may be a potential therapeutic target.

背景：主动脉夹层（Aortic夹层，AD）是一种以高发病率和高死亡率为特征的危及生命的心血管疾病。然而，细胞内pH在AD发生中的分子机制尚未完全阐明。本研究探讨了碳酸酐酶9 （CA9）在VSMCs胞内pH中的作用及其调控机制。方法：采用细胞计数试剂盒-8 （CCK-8）检测细胞活力，采用BCECF-AM探针检测细胞内pH。采用Cut &run-qPCR法检测HIF-1α对CA9转录的调控作用。采用RT-qPCR、Western blot和免疫荧光法检测CA9、HIF-1α、MMP2和α-SMA的表达水平。结果：我们的研究结果表明，CA9在AD组织中显著上调，主要定位于VSMCs，并与MMP2水平升高相关，而α-SMA水平下降。在VSMCs中沉默CA9导致细胞活力降低和细胞内ph升高。此外，我们发现HIF-1α在AD中上调，从而调节CA9在VSMCs中的表达。在bbapn诱导的小鼠模型中，JTC801治疗可降低CA9和HIF-1α的表达，提高生存率，降低AD发病率。结论：本研究确定CA9是AD患者pH失调的缺氧反应介质，由HIF-1α调节。JTC801靶向HIF-1α/CA9轴为恢复VSMC稳态和ECM完整性提供了一种新的治疗策略。这些发现促进了我们对阿尔茨海默病细胞内pH值的理解，并强调这种方法可能是一种潜在的治疗靶点。

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引用次数: 0

Inhibition of Pyk2 prevents Cx43 remodeling and cardiomyocyte injury during hypoxic and adrenergic stress 抑制Pyk2可防止缺氧和肾上腺素能应激时Cx43重塑和心肌细胞损伤

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-17 DOI: 10.1016/j.yjmcc.2025.12.006

Ming Ding , Li Zheng , Tapan A. Patel , Matthew C. Zimmerman , Kaushik P. Patel , Paul L. Sorgen

Hypoxia induces pathological remodeling in cardiomyocytes, in part by disrupting gap junction communication through Connexin43 (Cx43) phosphorylation and internalization. Here, we identify Proline-rich tyrosine kinase 2 (Pyk2) as a critical mediator of hypoxia- and adrenergic-induced Cx43 remodeling and cardiomyocyte dysfunction. Neonatal rat ventricular myocytes exposed to hypoxia (1 % O₂) for 1 or 24 h exhibited increased expression of hypoxia-inducible factor 1α and activated Pyk2 (pY402 and pY579/580), without changes in the total level of Pyk2. Hypoxia also enhanced Cx43 phosphorylation at Y265, a Pyk2-specific site, and increased expression of GJA1–20 k, an alternatively translated Cx43 isoform that supports Cx43 trafficking and mitochondrial function. Pharmacological Pyk2 inhibition with PF4618433 prevented hypoxia-induced Pyk2 activation, Cx43 phosphorylation, and attenuated the increase in GJA1–20 k expression. Immunofluorescence analysis revealed that hypoxia reduced Cx43 localization at intercellular junctions, an effect reversed by PF4618433 treatment. Functionally, Pyk2 inhibition reduced cell damage, as reflected by lower lactate dehydrogenase release and improved contractile activity. Mechanistically, PF4618433 attenuated apoptosis, oxidative stress, and preserved mitochondrial membrane potential, consistent with improved mitochondrial function. Furthermore, norepinephrine-induced Pyk2 activation and Cx43 Y265 phosphorylation were comparably suppressed by PF4618433, linking Pyk2 to both hypoxic as well as adrenergic stress signaling in cardiomyocytes. These findings demonstrate that Pyk2 activation promotes Cx43 downregulation, contributing to cardiomyocyte injury under hypoxic and adrenergic stress. Inhibition of Pyk2 preserves gap junction integrity, maintains mitochondrial function, and enhances cell survival, supporting Pyk2 as a promising therapeutic target in cardiac injury.

缺氧诱导心肌细胞病理性重构，部分原因是通过连接蛋白43 （Cx43）磷酸化和内化破坏间隙连接通讯。在这里，我们发现富含脯氨酸的酪氨酸激酶2 （Pyk2）是缺氧和肾上腺素能诱导的Cx43重塑和心肌细胞功能障碍的关键介质。新生大鼠心室肌细胞暴露于缺氧（1% O₂）1或24小时后，缺氧诱导因子1α的表达增加，Pyk2 （pY402和pY579/580）被激活，但Pyk2的总水平没有变化。缺氧还增强了pyk2特异性位点Y265的Cx43磷酸化，并增加了gja1 - 20k的表达，gja1 - 20k是一种可替代翻译的Cx43异构体，支持Cx43运输和线粒体功能。PF4618433抑制Pyk2抑制缺氧诱导的Pyk2活化和Cx43磷酸化，并减弱gja1 - 20k表达的增加。免疫荧光分析显示，缺氧降低了Cx43在细胞间连接处的定位，PF4618433治疗逆转了这一作用。在功能上，Pyk2抑制减少了细胞损伤，这反映在乳酸脱氢酶释放降低和收缩活性提高上。从机制上讲，PF4618433减轻了细胞凋亡、氧化应激，并保存了线粒体膜电位，与线粒体功能的改善一致。此外，去甲肾上腺素诱导的Pyk2激活和Cx43 Y265磷酸化被PF4618433抑制，这将Pyk2与心肌细胞中的缺氧和肾上腺素能应激信号联系起来。这些发现表明，Pyk2激活促进Cx43下调，有助于缺氧和肾上腺素能应激下心肌细胞损伤。抑制Pyk2可以保持间隙连接的完整性，维持线粒体功能，提高细胞存活率，支持Pyk2作为心脏损伤的有希望的治疗靶点。

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引用次数: 0

Corrigendum to “Age-related structural and functional changes of the intracardiac nervous system” Journal of Molecular and Cellular Cardiology, Volume 187 (2024) 1–14] “与年龄相关的心内神经系统结构和功能变化”的勘误表《分子和细胞心脏病学杂志》，187卷（2024）1-14]。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-09 DOI: 10.1016/j.yjmcc.2025.11.010

Eliza Sassu , Gavin Tumlinson , Dragana Stefanovska , Marbely C. Fernández , Pia Iaconianni , Josef Madl , Tomás A. Brennan , Manuel Koch , Breanne A. Cameron , Sebastian Preissl , Ursula Ravens , Franziska Schneider-Warme , Peter Kohl , Callum M. Zgierski-Johnston , Luis Hortells

引用次数: 0

Extracellular-cAMP suppresses pulmonary arterial hypertension-induced ventricular arrhythmias 细胞外camp抑制肺动脉高压引起的室性心律失常。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-08 DOI: 10.1016/j.yjmcc.2025.12.004

Marine Cacheux , Benjamin Strauss , Shestruma Parajuli , Aymen Halouani , Michael G. Katz , Seun Imani , Samar Antar , Nestor Bedoya , Lahouaria Hadri , Fadi G. Akar , Yassine Sassi

Pulmonary Arterial Hypertension (PAH), a major cause of right ventricular failure, is associated with a high 5-year mortality rate. Arrhythmias account for a significant proportion of morbidity and mortality in PAH patients. Hence, there is a critical need for new therapies to effectively treat PAH-related cardiac arrhythmias. The purpose of this study was to evaluate the efficacy of extracellular cyclic adenosine monophosphate (e-cAMP) treatment in reversing pathophysiological electrophysiological (EP) remodeling and arrhythmia propensity caused by PAH. Ex-vivo optical action potential (AP) mapping, real-time reverse transcription–polymerase chain reaction, immunostaining, morphological and histologic analyses were performed on two different models of pulmonary hypertension (Monocrotaline and Sugen/pneumonectomy) to test the impact of e-cAMP treatment in suppressing ventricular arrhythmias in PAH. PAH diseased rats from both models exhibited a high propensity of inducible ventricular tachycardia (VT). Remarkably, e-cAMP treatment suppressed the incidence of VT in both models. Examination of the EP substrate revealed action potential duration prolongation and marked conduction slowing in PAH-diseased animals. These features, however, were significantly reversed by e-cAMP treatment. Moreover, e-cAMP reversed the development of AP alternans in PAH. Extracellular cAMP-treated rats exhibited a significant decrease in myocardial fibrosis and hypertrophic remodeling. Reversal of EP remodeling by e-cAMP was accompanied by decreased pulmonary vascular remodeling and by restored cardiac expression of key ion channel transcripts. Extracellular cAMP treatment reduces the incidence of ventricular arrhythmias and suppresses pathological EP remodeling by restoring cardiac and pulmonary vascular remodeling. This approach may represent a new therapeutic modality for arrhythmia suppression in PAH patients.

肺动脉高压（PAH）是导致右心室衰竭的主要原因，与高5年死亡率相关。心律失常在PAH患者的发病率和死亡率中占很大比例。因此，迫切需要新的治疗方法来有效治疗pah相关的心律失常。本研究的目的是评估细胞外环磷酸腺苷（e-cAMP）治疗对逆转PAH引起的病理生理电生理（EP）重塑和心律失常倾向的疗效。对两种不同的肺动脉高压模型（Monocrotaline和Sugen/pneumonectomy）进行体外光动作电位（AP）作图、实时逆转录聚合酶链反应、免疫染色、形态学和组织学分析，以检验e-cAMP治疗对PAH室性心律失常的抑制作用。两种模型的PAH病变大鼠均表现出高诱发性室性心动过速（VT）的倾向。值得注意的是，e-cAMP治疗抑制了两种模型的VT发生率。EP底物检测显示，pah患病动物的动作电位持续时间延长，传导明显减慢。然而，e-cAMP治疗显著逆转了这些特征。此外，e-cAMP逆转了PAH中AP突变体的发展。细胞外camp处理的大鼠心肌纤维化和肥厚重塑明显减少。e-cAMP对EP重塑的逆转伴随着肺血管重塑的减少和心脏关键离子通道转录物表达的恢复。细胞外cAMP治疗可减少室性心律失常的发生率，并通过恢复心脏和肺血管重塑来抑制病理性EP重塑。这种方法可能是抑制PAH患者心律失常的一种新的治疗方式。

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引用次数: 0

Galangin alleviates cardiac ischemia/reperfusion injury in human iPSC-derived cardiomyocytes and animal models 高良姜可减轻人ipsc源性心肌细胞和动物模型的心肌缺血/再灌注损伤。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-05 DOI: 10.1016/j.yjmcc.2025.12.003

Yongjun Wang , Shane R. Zhao , Dong Han , Wenshu Zeng , Mohamed Rafiuddin Ahmed , Xulei Qin , Qiang Liu , Joe Z. Zhang , Jayakumar Rajadas , Joseph C. Wu

引用次数: 0

Human atrial skinned muscle fibers exhibit reduced length-dependent activation but show faster force development kinetics than ventricular muscle 人心房皮肌纤维表现出减少的长度依赖性激活，但表现出比心室肌更快的力量发展动力学。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-04 DOI: 10.1016/j.yjmcc.2025.12.001

Alexandre Lewalle , Gregory Milburn , Jania Bell , Kenneth S. Campbell , Steven A. Niederer

In humans, the left atria (LA) and the left ventricle (LV) play distinct physiological roles and express sarcomeric proteins with chamber-specific patterns. Despite these important differences, most multi-chamber descriptions of the heart assume uniform myocardial properties. To facilitate a more accurate representation of cardiac function, we measured and compared the contractile properties of isolated skinned human LA and LV muscle fibers at 37

° C

. Our experimental measurements included the length-dependent activation (LDA) of force in the isometric steady state, the force response to small quick length changes, and tension redevelopment dynamics. The LV measurements display more pronounced LDA behavior compared to LA, whereas the LA dynamics is generally faster than LV.

To elucidate these differences mechanistically, we used the LA and LV experimental datasets to fit a biophysical model framework to produce a representative model for each chamber. Our Bayesian statistical approach aimed to maximize the objectivity of the model calibrations and to allow a systematic assessment of chamber-specific parameter differences. Passive mechanical properties emerge as the principal determinant of LDA behavior. However, variations in cross-bridge cycling kinetics account more significantly for LA/LV differences in the ATP consumption to produce a given isometric force.

These results constitute the first systematic biophysical comparison of LA and LV cardiomyocyte contraction mechanics in humans, paving the way to further investigation of their roles within the broader cardiovascular physiological context.

在人类中，左心房（LA）和左心室（LV）发挥着不同的生理作用，并表达具有腔室特异性模式的肌肉蛋白。尽管存在这些重要的差异，大多数对心脏的多腔室描述都假定心肌的特性是一致的。为了更准确地表示心功能，我们测量并比较了37°C下皮肤分离的人左室和左室肌肉纤维的收缩特性。我们的实验测量包括等距稳定状态下力的长度相关激活（LDA），小的快速长度变化的力响应以及张力再开发动态。LV测量结果显示出比LA更明显的LDA行为，而LA动力学通常比LV更快。为了从机制上阐明这些差异，我们使用LA和LV实验数据集拟合生物物理模型框架，为每个腔室生成具有代表性的模型。我们的贝叶斯统计方法旨在最大限度地提高模型校准的客观性，并允许对腔室特定参数差异进行系统评估。被动力学性能成为LDA行为的主要决定因素。然而，跨桥循环动力学的变化更显著地解释了产生给定等距力的ATP消耗的LA/LV差异。这些结果构成了人类左心室和左心室心肌细胞收缩机制的第一个系统的生物物理比较，为进一步研究它们在更广泛的心血管生理背景下的作用铺平了道路。

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引用次数: 0

Single cell transcriptomic landscape of adult and pediatric non-ischemic cardiomyopathy 成人和儿童非缺血性心肌病的单细胞转录组学景观。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-04 DOI: 10.1016/j.yjmcc.2025.12.002

Hanna J. Tadros , Diwakar Turaga , Kyle Hope , Joseph A. Spinner , Iki Adachi , Xiao Li , James F. Martin

Non-ischemic cardiomyopathy (NICM) is a devastating diagnosis with a wide array of phenotypes, ranging from mild cardiac hypertrophy to end-stage heart failure. Single-cell/nucleus RNA sequencing technologies have expanded and become a necessary tool to unravel the transcriptome across thousands to millions of cells. Studies incorporating these technologies to examine pediatric and adult myocardium have improved our understanding of underlying pathophysiology in cardiomyopathy, identified novel gene and genetic pathway associations, and paved the way for precision medicine therapeutics in cardiovascular medicine. We compiled the recent literature that showcase single cell/nucleus technologies in NICM in adult and pediatric populations and describe cell type-specific changes, ultimately setting the stage for future targeted gene manipulation/precision medicine.

非缺血性心肌病（NICM）是一种具有广泛表型的破坏性诊断，从轻度心脏肥厚到终末期心力衰竭。单细胞/细胞核RNA测序技术已经扩展并成为揭示数千到数百万细胞转录组的必要工具。结合这些技术检查儿童和成人心肌的研究提高了我们对心肌病潜在病理生理学的理解，发现了新的基因和遗传途径关联，并为心血管医学的精准医学治疗铺平了道路。我们汇编了最近的文献，展示了单细胞/细胞核技术在成人和儿童NICM人群中的应用，并描述了细胞类型特异性变化，最终为未来的靶向基因操作/精准医学奠定了基础。

引用次数: 0

Corrigendum to ‘FABP4, marker of worse prognosis in cardiovascular disease, induces neutrophil’s proatherogenic phenotype which is modulated by semaglutide’ [Journal of Molecular and Cellular Cardiology volume 210 (2026) 12–27] “FABP4，心血管疾病预后较差的标志物，诱导中性粒细胞的促动脉粥样硬化表型，这是由semaglutide调节的”[Journal of Molecular and Cellular Cardiology vol 210(2026) 12-27]的更正。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-12-03 DOI: 10.1016/j.yjmcc.2025.11.015

David Sánchez-López , David García-Vega , J.E. Viñuela , Isabel Ferreirós-Vidal , Diego Iglesias-Álvarez , José Manuel Martínez-Cereijo , Laura Reija-López , Ángel L. Fernández-González , José R. González-Juanatey , Sonia Eiras

引用次数: 0

ZIP14 upregulation leads to ferroptosis and lysosomal dysfunction through intracellular iron overload and induces myocardial ischemia/reperfusion injury in mouse hearts ZIP14上调通过细胞内铁超载导致小鼠心肌铁上吊和溶酶体功能障碍，诱导心肌缺血/再灌注损伤。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-27 DOI: 10.1016/j.yjmcc.2025.11.014

Liang Zhao , Yuru Cao , Xianle Liu , Qing Yang , Zhelong Xu

While the ZIP family Zn²⁺ transporters such as ZIP2 and ZIP7 play critical roles in myocardial ischemia/reperfusion (I/R) injury by regulating Zn²⁺ homeostasis, little is known about the roles of the other ZIP family Zn²⁺ transporters in I/R injury. Here we report that ZIP14, a ZIP family Zn²⁺ transporter, contributes to the pathogenesis of myocardial I/R injury by controlling Fe²⁺ homeostasis.

Mouse hearts were subjected to I/R in vivo. Lipid peroxides were measured with C11-BODIPY and MDA. Infarct size was measured with the TTC staining. The cardiac-specific ZIP14 knockdown (AAV-shZIP14) and overexpression (AAV-ZIP14) mice were generated by adopting the AAV system. AAV-shZIP14 decreased but AAV-ZIP14 increased Fe²⁺ levels in cardiomyocytes. ZIP14 is upregulated at reperfusion, and AAV-shZIP14 reduced but AAV-ZIP14 enhanced ferroptosis caused by I/R. ZIP14 upregulation led to lysosomal lipid peroxidation in a Fe²⁺-dependent manner, which ultimately contributes to myocardium injury by causing lysosomal membrane permeabilization (LMP) and impairment of autophagic flux.

Our findings identify upregulation of ZIP14 leading to ferroptosis, LMP, and suppression of autophagic flux as a critical feature of myocardial I/R injury. Targeting cardiac ZIP14 upregulation may serve as a therapeutic strategy for the treatment of myocardial I/R injury.

虽然ZIP2和ZIP7等ZIP家族Zn2+转运蛋白通过调节Zn2+稳态在心肌缺血再灌注（I/R）损伤中起关键作用，但对其他ZIP家族Zn2+转运蛋白在I/R损伤中的作用知之甚少。本文报道了ZIP家族Zn2+转运蛋白ZIP14通过控制Fe2+稳态参与心肌I/R损伤的发病机制。小鼠心脏在体内进行I/R。用C11-BODIPY和MDA测定脂质过氧化物。TTC染色测定梗死面积。采用AAV系统制备心脏特异性ZIP14敲低（AAV- shzip14）和过表达（AAV-ZIP14）小鼠。AAV-shZIP14降低心肌细胞Fe2+水平，而AAV-ZIP14升高心肌细胞Fe2+水平。再灌注时ZIP14上调，AAV-shZIP14降低，但AAV-ZIP14增强I/R所致的铁下垂。ZIP14上调导致溶酶体脂质以Fe2+依赖的方式过氧化，最终导致溶酶体膜透性（LMP）和自噬通量受损，从而导致心肌损伤。我们的研究结果表明，ZIP14的上调导致铁下垂、LMP和自噬通量的抑制是心肌I/R损伤的一个关键特征。靶向心脏ZIP14上调可能是治疗心肌I/R损伤的一种治疗策略。

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引用次数: 0

Cyclic AMP-dependent regulation of ryanodine receptors in healthy and diseased hearts 健康和患病心脏中ryanodine受体的环amp依赖性调节。

IF 4.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of molecular and cellular cardiology

Pub Date : 2025-11-24 DOI: 10.1016/j.yjmcc.2025.11.013

Mohit M. Hulsurkar , Isabelle Ong , Joshua A. Keefe , Issam H. Abu-Taha , Dobromir Dobrev , Xander H.T. Wehrens

Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca²⁺-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca²⁺ release, and cardiac arrhythmias. Furthermore, cAMP influences the expression of Ca²⁺-handling proteins. This review examines the mechanisms governing cAMP levels in the sarcoplasmic reticulum nanodomain and their role in regulating RyR2 function in healthy and diseased hearts.

环腺苷一磷酸（cAMP）是心肌细胞中关键的第二信使，调节基本细胞功能。在g蛋白偶联受体刺激下，腺苷酸环化酶（AC）合成cAMP，随后磷酸二酯酶（PDE）降解cAMP。最近的研究挑战了统一cAMP信号的传统观点，揭示了心肌细胞内纳米结构域特异性调控。这种定位的cAMP信号通过通道结合蛋白激酶和pde调节关键的Ca2+处理蛋白，包括RyR2 （RyR2）。此外，核苷二磷酸激酶（ndpk），特别是NDPK-C，参与cAMP合成和RyR2调控。心力衰竭患者NDPK-C水平升高与cAMP水平升高、肌浆网Ca2+释放增强和心律失常相关。此外，cAMP影响Ca2+处理蛋白的表达。本文综述了肌浆网纳米结构域cAMP水平的调控机制及其在健康和患病心脏中调节RyR2功能的作用。

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