Circulation research最新文献

{"title":"Correction to: BMX Represses Thrombin-PAR1-Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis.","authors":"Zhao Li, Mingzhu Yin, Haifeng Zhang, Weiming Ni, Richard W Pierce, Huanjiao Jenny Zhou, Wang Min","doi":"10.1161/RES.0000000000000723","DOIUrl":"https://doi.org/10.1161/RES.0000000000000723","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 3","pages":"e63"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Enhancement of Small Conductance Ca²⁺-Activated K⁺ Channels Suppresses Cardiac Arrhythmias in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia.","authors":"Roland Veress, Radmila Terentyeva, Andriy E Belevych, Fruzsina Perger, Zuzana Nichtova, Anastasia Pokrass, Yujia Cheng, Snizhana Chorna, Isabelle Deschenes, Sandor Gyorke, Bjorn C Knollmann, Richard T Clements, Harpreet Singh, Bin Liu, Gyorgy Csordas, Shanna Hamilton, Dmitry Terentyev","doi":"10.1161/CIRCRESAHA.124.325477","DOIUrl":"10.1161/CIRCRESAHA.124.325477","url":null,"abstract":"<p><strong>Background: </strong>Sarcolemmal small conductance Ca²⁺-activated K⁺ channels have the unique capacity to translate intracellular Ca²⁺ signal into repolarization, while mitochondrial SK channels can link Ca²⁺ cycling to mitochondrial function. We hypothesize that pharmacological enhancement of SK channels can be protective against malignant cardiac arrhythmias associated with disturbances in Ca²⁺ handling machinery.</p><p><strong>Methods: </strong>A mouse CASQ2 KO (calsequestrin type 2 knockout) model of catecholaminergic polymorphic ventricular tachycardia (CPVT) was used for in vivo ECG recordings and for cell electrophysiology, Ca²⁺, and reactive oxygen species imaging in isolated ventricular myocytes (VMs).</p><p><strong>Results: </strong>Bidirectional and polymorphic ventricular tachycardias in CASQ2 KO mice induced by stress challenge (epinephrine+caffeine cocktail) were attenuated by injection of NS309, a specific SK channel enhancer. Voltage-clamp experiments in isolated VMs treated with β-adrenergic agonist isoproterenol showed a reduction of sarcolemmal SK channel current (I_SK) density in CPVT VMs. Application of NS309 to CPVT VMs increased I_SK. Current-clamp experiments demonstrated a significant reduction of arrhythmogenic delayed afterdepolarizations and spontaneous Ca²⁺ waves in isoproterenol-challenged CPVT VMs pretreated with NS309. Importantly, subsequent application of membrane-impermeable SK channel inhibitor apamin did not reverse the protective effects of NS309, suggesting important roles of mitochondrial SK channels in intracellular Ca²⁺ handling rescue. SK channel enhancement reversed the increased rate of reactive oxygen species production by mitochondria in CPVT VMs. It also reversed increased cardiac RyR2 (ryanodine receptor 2) oxidation measured in samples from CPVT hearts of the animals after the stress challenge. Electron microscopy studies showed a significant widening of mitochondria cristae in the ventricular tissue from CPVT mice, which led to a decrease in quaternary supercomplexes of electron transport chain, resulting in impairment of ATP production in VMs under β-adrenergic stimulation. Application of NS309 facilitated cristae flattening in CPVT ventricular tissue and restored supercomplexes and ATP production in VMs from diseased animals.</p><p><strong>Conclusions: </strong>Sarcolemmal SK channel enhancement reduces arrhythmic potential by restoring repolarization force in CPVT VMs. Activation of mitochondrial SK channels attenuates mitochondria structural changes in CPVT, restoring more efficient electron transport chain assembly into supercomplexes and reducing mito-reactive oxygen species production. This decreases RyR2 oxidation and thus channel activity, reducing spontaneous Ca²⁺ waves underlying arrhythmogenic delayed afterdepolarizations.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"386-399"},"PeriodicalIF":16.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Rpl13a snoRNAs U34 and U35a: New Targets for Sickle Cell Disease Complications.","authors":"Waseem Chauhan,Sudharshan Setra Janardhana Shetty,Shirin Ferdowsi,Sweta Kafle,Rahima Zennadi","doi":"10.1161/res.0000000000000726","DOIUrl":"https://doi.org/10.1161/res.0000000000000726","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"9 1","pages":"e64"},"PeriodicalIF":20.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arrhythmogenic Cross-Talk in the Ischemic Heart.","authors":"Ruben Coronel,Lisa A Gottlieb","doi":"10.1161/circresaha.125.326833","DOIUrl":"https://doi.org/10.1161/circresaha.125.326833","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"30 1","pages":"383-385"},"PeriodicalIF":20.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological Significance of Endothelial M3 Muscarinic Receptors During Exercise.","authors":"Gareth L Ackland,Patrick S Hosford,Ana Gutierrez Del Arroyo,Alla Korsak,Asif Machhada,Jack Pickard,Genoveva Gomez Gomez De La Torre,Daniel J Stuckey,Andrew Tinker,Andrew B Tobin,Jongrye Jeon,Jürgen Wess,Alexander V Gourine","doi":"10.1161/circresaha.125.326589","DOIUrl":"https://doi.org/10.1161/circresaha.125.326589","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"2 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vagal Stimulation Rescues HFpEF by Altering Cardiac Resident Macrophage Function.","authors":"Thamizhiniyan Venkatesan,Maria Toumpourleka,Monika Niewiadomska,Kassem Farhat,Lynsie Morris,Khaled Elkholey,Bibi Maryam,Audrey Cordova,Isabella G Darby,Seabrook Whyte,Sarah J Miller,Alex Yashchenko,Alex C Anguiano,Jenny Gipson,Jessica M Reel,Maureen A Cox,Kurt A Zimmerman,Stavros Stavrakis","doi":"10.1161/circresaha.125.326236","DOIUrl":"https://doi.org/10.1161/circresaha.125.326236","url":null,"abstract":"BACKGROUNDWe previously showed in a rat model of heart failure with preserved ejection fraction (HFpEF) that transcutaneous vagus nerve stimulation (tVNS) reduced cardiac fibrosis and inflammation. However, macrophage-mediated mechanisms through which tVNS rescues cardiac function remain poorly understood.METHODSWe induced HFpEF in 8-week-old mice by a combination of a high-fat diet and l-NG-nitro arginine methyl ester for 5 weeks, followed by 4 weeks of tVNS or sham stimulation. At this time, we analyzed cardiac function by echocardiography and immune cell numbers by single-cell RNA sequencing and flow cytometry.RESULTSOur data demonstrate that HFpEF mice exhibited diastolic dysfunction, left ventricular hypertrophy, and fibrosis, consistent with HFpEF, and that tVNS significantly improved HFpEF severity. Analysis of merged single-cell RNA sequencing data from control, HFpEF+sham, and HFpEF+tVNS mice showed that HFpEF was associated with the accumulation of Spp1-expressing CCR2 (C-C chemokine receptor type 2)+ cardiac resident macrophages (CRM). Furthermore, treatment with tVNS reduced the number of CCR2+ CRM and the expression of Spp1 while also inducing the expression of Igf1 in TLF+ (Timd4+/Lyve1+/Folr2+) and MHC2+ CRM. Global deletion of Spp1 or blockade of CCR2+ CRM recruitment improved HFpEF, whereas TLF+/MHC2+ specific deletion of Igf1 reversed the protective effect of tVNS on HFpEF. The benefits of tVNS were also abolished in the setting of disrupted acetylcholine/α7nAChR (α7 neuronal acetylcholine receptor) signaling, either via pharmacological inhibition of α7nAChR or choline acetyltransferase deletion in CD4+ T cells.CONCLUSIONSCollectively, our data indicate that tVNS improves HFpEF by reducing Spp1 expressing CCR2+ CRM and inducing expression of proreparative Igf1 in TLF+/MHC2+ CRM. These effects are mediated through cholinergic signaling, highlighting a neuroimmune pathway in HFpEF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"29 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combinatory Treatment to Alleviate Cellular Stress and Improve Skeletal Muscle Phenotype in Spinal Muscular Atrophy.","authors":"Wenshu Zeng,Xiaohui Kong,Arianne Caudal,Shane Rui Zhao,Christina Alamana,Juan Melesio,Lu Ren,Jessica Guzman,Paul D Pang,Kelly Howell,Karen S Chen,John W Day,Joseph C Wu","doi":"10.1161/circresaha.124.325931","DOIUrl":"https://doi.org/10.1161/circresaha.124.325931","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Androgen Receptor Governs Tip Cell Formation in Cerebrovascular Malformations.","authors":"Ruofei Li,Liang Yu,Mengchen Xu,Xiao Xiao,Yushan Tang,Cheng Lv,Yu Zhang,Tao Hong,Yibo Wang","doi":"10.1161/circresaha.125.326471","DOIUrl":"https://doi.org/10.1161/circresaha.125.326471","url":null,"abstract":"BACKGROUNDCerebrovascular malformations are a pivotal cause of hemorrhage and neurological disability, orchestrated largely by aberrant vascular homeostasis. However, a malformed angiogenic regulation pattern remains elusive.METHODSSingle-cell transcriptome analysis uncovered the endothelial features of human cerebral cavernous malformations and brain arteriovenous malformations, 2 typical cerebrovascular malformation diseases. Endothelial AR (androgen receptor, a steroid receptor in the nuclear receptor superfamily) overexpression was conducted to investigate its involvement in tip cell formation. ARD-2585, an AR degradator, was applied to mouse models of cerebral cavernous malformations (endothelial-specific Pdcd10 knockout mice) and brain arteriovenous malformations (endothelial-specific KrasG12D mutant [KrasG12D] mice) to evaluate its vascular rescue potential.RESULTSWe profiled single-cell transcriptomes of 13 human cerebrovascular malformation samples (10 cerebral cavernous malformations and 3 brain arteriovenous malformations) and 13 control brain samples, identifying a crucial pathological tip cell population in lesions. Integrative bioinformatics revealed a systemic endothelial regulatory network, with AR as a key regulator of this aberrant state. AR expression was elevated in endothelial cells from both human cerebrovascular malformations and Pdcd10 knockout/KrasG12D mice, correlating with suppressed DLL4 (delta-like canonical Notch ligand 4)-Notch signaling. AR overexpression augmented endothelial tube formation, filopodia extension, and polarization in vitro and fostered sex-independent vascular sprouting in vivo. High levels of AR facilitated proangiogenic gene transcription by recruiting coactivators EP300 (EP300 lysine acetyltransferase)/CBP (CREB binding lysine acetyltransferase), augmenting histone H3 lysine 18/histone H3 lysine 27 acetylation, and boosting chromatin accessibility, potentially independent of androgen. Notably, ARD-2585 treatment effectively normalized vascular anomalies and alleviated cerebral hemorrhage in Pdcd10 knockout and KrasG12D mice.CONCLUSIONSWe delineated a novel androgen-independent AR-mediated endothelial sprouting pattern in malformed cerebrovasculature, highlighting a promising foundation for developing interventions targeting tip cells in angiogenic diseases.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"22 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arterial Myocyte Pannexin 1 Channel Controls Vascular Reactivity in Diabetic Hyperglycemia.","authors":"Junyoung Hong,Miguel Martín-Aragón Baudel,Sayeman Islam Niloy,Jade Taylor,Yaseen Mohabbat,Yumna Moustafa,Eric Pereira Da Silva,Brooke L O'Donnell,Zhenduo Zhu,Nuria Daghbouche-Rubio,Gopyreddy R Reddy,Kent C Sasse,Sean M Ward,Yang K Xiang,Brant E Isakson,Madeline Nieves-Cintrón,Manuel F Navedo","doi":"10.1161/circresaha.125.326260","DOIUrl":"https://doi.org/10.1161/circresaha.125.326260","url":null,"abstract":"BACKGROUNDDiabetic hyperglycemia promotes vasoconstriction by activating an ATP-dependent P2Y11L (P2Y11-like receptor)/AC5 (adenylyl cyclase 5)/AKAP5 (A-kinase anchoring protein 5)/PKA (protein kinase A)/CaV1.2 (L-type voltage-dependent calcium channel 1.2) nanocomplex in arterial myocytes, but upstream mechanisms are unclear. We hypothesized that Panx1 (pannexin 1) channels, which facilitate ATP release, are associated with the complex in arterial myocytes and mediate its activation to induce vasoconstriction on diabetic hyperglycemia.METHODSMultidisciplinary approach using extracellular ATP and cAMP biosensors, patch-clamp electrophysiology, super-resolution nanoscopy, proximity ligation assay, pressure myography, and laser speckle imaging to test premises in arterial myocytes and vessels from wild-type and genetically modified mice, including an inducible smooth muscle-specific Panx1 knockout and a global AKAP5 knockout.RESULTSWe found that elevating extracellular glucose (eg, high glucose, hyperglycemia) triggered an increase in extracellular ATP levels, and this was reduced in the presence of the Panx1 inhibitor spironolactone, in inducible smooth muscle-specific Panx1 knockout cells, and by inhibiting glucose metabolism. Panx1 was found in complex with P2Y11L, AC5, AKAP5, PKA, and CaV1.2 in arterial myocytes. The protein complex was strengthened in response to high glucose, hyperglycemia, which required Panx1 and AKAP5. High glucose, hyperglycemia-induced cAMP production, CaV1.2 potentiation, sustained vasoconstriction, and in vivo changes in cerebral artery myogenic tone and blood flow were ameliorated by spironolactone and in inducible smooth muscle-specific Panx1 knockout samples. Panx1 expression was elevated in arterial lysates from a mouse model of type 1 diabetes (eg, streptozotocin), and increased CaV1.2 activity and enhanced ex vivo and in vivo myogenic tone were prevented in arterial myocytes and arteries from inducible smooth muscle-specific Panx1 knockout mice.CONCLUSIONSThese results suggest a key role for Panx1 in controlling ATP signaling through the P2Y11L/AC5/AKAP5/PKA/CaV1.2 axis in arterial myocytes. This Panx1-led complex modulates cAMP levels, CaV1.2 activity, and vascular reactivity in response to diabetic hyperglycemia. Thus, Panx1 could be a new therapeutic target to mitigate vascular complications during diabetes.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"20 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-3154: Novel Pathogenic and Therapeutic Target in Abdominal Aortic Aneurysm.","authors":"QingBin Hou,Yisi Liu,Jingjin Hou,Haixu Song,Sijia Zhang,Yan Zhang,Jing Liu,Xiaoling Zhang,Yong Ji,Chenghui Yan,Yaling Han","doi":"10.1161/circresaha.124.325256","DOIUrl":"https://doi.org/10.1161/circresaha.124.325256","url":null,"abstract":"BACKGROUNDAbdominal aortic aneurysm (AAA) is a life-threatening condition with no effective pharmacological treatments currently available, likely due to our incomplete understanding of the molecular mechanisms underlying AAA pathogenesis and progression. In many cardiovascular diseases, circulatory microRNAs are potential diagnostic and prognostic biomarkers. Therefore, we investigated novel microRNAs with diagnostic and therapeutic potential in AAA.METHODSWe performed microRNA expression analysis in aorta specimens isolated from mice with saline-induced or Ang II (angiotensin II)-induced AAA, wherein microRNA-3154 (miR-3154) was identified as a potential key molecule in AAA pathogenesis. We used RNA-sequencing analysis, cell migration assays, immunoblotting, protein interactome analysis, coimmunoprecipitation, molecular docking, and molecular dynamics simulation to determine the role of miR-3154 in AAA pathogenesis, clarify the phenotype, and elucidate the underlying molecular mechanisms.RESULTSUsing high-throughput sequencing, miR-3154 was identified in the aortic tissue of ApoE-/- mice with AAA as compared with control mice. Increased miR-3154 expression was confirmed in the early-stage Ang II-induced AA mouse model and the aortic tissues of patients with AAA. Patients with AAA had higher serum miR-3154 level, which positively correlated with computed tomography-estimated size of the aneurysm. Functionally, miR-3154 dose-dependently aggravated vascular smooth muscle cell phenotypic switching and AAA development, both in vivo and in vitro. In vascular smooth muscle cells, TNS1 (tensin-1) was identified as a direct target of miR-3154. Mechanistically, TNS1 interacts with the R1-R13 domain of TLN1 (talin-1), thereby suppressing Sp1 (specificity protein 1) phosphorylation at Thr739 and upregulating MEOX1 (mesenchyme homeobox 1) expression-a key transcription factor regulating vascular smooth muscle cell phenotypic switching.CONCLUSIONSWe uncovered a novel pathogenic role of miR-3154 in AAA, suggesting its potential as both a therapeutic target and prognostic biomarker.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"21 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}