Circulation research最新文献

{"title":"SLC39A13 Regulates Heart Function via Mitochondrial Iron Homeostasis Maintenance.","authors":"Huihui Li,Xiaoting Wang,Yu Zhang,Yuan Yang,Joe Z Zhang,Bing Zhou","doi":"10.1161/circresaha.125.326201","DOIUrl":"https://doi.org/10.1161/circresaha.125.326201","url":null,"abstract":"BACKGROUNDIron is a necessary trace element for multiple reactions but is toxic in excess. Its intracellular balance is delicately maintained. We previously found that the loss of SLC39A13 (ZIP13), a newly identified endoplasmic reticulum/Golgi-resident iron transporter, impacted iron homeostasis in multiple tissues. The purpose of this study is to investigate the role of ZIP13 in regulating cardiac functions and the precise mechanism of cardiac injury caused by ZIP13 deficiency.METHODSCardio-specific knockout of Zip13 (Zip13-CKO), tamoxifen-inducible Zip13 knockout (Zip13-iKO), and systemic (germline) Zip13 knockout mouse model were used to study the effect of Zip13 deletion on cardiac functions. These mice were analyzed for growth, cardiac systolic function, mitochondrial morphology, mitochondrial iron metabolism, and mitochondrial biogenesis and activity. We also generated cardio-specific ferroportin 1 (Fpn1-CKO) and Zip13&Fpn1 (Zip13&Fpn1-CKO) double-knockout mice to compare with Zip13-CKO mice. Mouse embryonic fibroblasts and primary cardiomyocytes were used for in vitro experiments.RESULTSZip13-CKO mice displayed severe cardiac systolic dysfunctions. The mitochondrial function and morphology were markedly abnormal in Zip13-CKO cardiomyocytes, accompanied by cytosolic iron increase and mitochondrial iron decrease. These were also confirmed in vitro with mouse embryonic fibroblasts and primary cardiomyocytes. Moreover, iron supplementation or overexpressing MFRN1 (mitoferrin 1), a mitochondrial iron importer, could substantially restore the mitochondrial iron homeostasis and function of ZIP13-deficient primary cardiomyocytes, indicating mitochondrial iron dyshomeostasis underlies the observed cardiac abnormality. The Zip13-CKO did not wholly resemble that of Fpn1-CKO, which was associated with elevated cytosolic iron, but no statistically significant change was observed in mitochondrial iron. Zip13&Fpn1-CKO mice presented a more severe heart defect than either single mutant alone, likely due to a further aggravated iron accumulation in the cytosol of cardiomyocytes.CONCLUSIONSWe propose that ZIP13 and FPN1 are both required to maintain cardiac functions via overlapping but different manners; FPN1 maintains the cytosolic iron by exporting iron out of the cells, while ZIP13 helps balance the iron equilibrium between the cytosol and the organellar network system, including the mitochondrion. These findings establish the critical role of ZIP13 in maintaining mitochondrial iron homeostasis and activity, enabling cardiomyocytes to perform effectively their essential roles.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"26 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720167","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":"Circulating Immune Cell Signature Analysis in HFpEF Across Species.","authors":"Jasmin M Kneuer,Marion Müller,Stephan Erbe,Karoline E Kokot,Sebastian Rosch,Irina Müller-Kozarez,Sophie Charlotte Schrö,Christina Maeder,Sarah Felicitas Heitkamp,Susanne Gaul,Stephan von Haehling,Anke Tönjes,Matthias Blüher,Philipp Lurz,Rolf Wachter,Anna Klinke,Ulrich Laufs,Jes-Niels Boeckel","doi":"10.1161/circresaha.125.326249","DOIUrl":"https://doi.org/10.1161/circresaha.125.326249","url":null,"abstract":"BACKGROUNDHeart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension, and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of patients with HFpEF showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment-specific patterns.METHODSWe performed single-cell RNA sequencing of peripheral blood mononuclear cells of patients with HFpEF (n=6), heart failure with reduced ejection fraction patients (n=8), and healthy controls (n=7), taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in an HFpEF mouse model (induced by a high-fat diet plus L-NAME), with one group additionally administered the anti-inflammatory agent nitro-oleic acid.RESULTSAnalysis of human peripheral blood mononuclear cells revealed an HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (eg, CCL2 and TNF) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with nitro-oleic acid leading to a partial normalization of immunologic signatures and a significant improvement in diastolic function.CONCLUSIONSOur results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with heart failure with reduced ejection fraction analyzed in this study. The conserved immunologic signatures between the human and murine data sets analyzed here, and the beneficial effect of nitro-oleic acid in the preclinical model induced by high-fat diet and L-NAME, provide translational insights and generate hypotheses for personalized interventions in HFpEF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"52 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701084","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":"Early Stage Morphogenesis of Transverse Tubules in Rat Cardiomyocytes: The Role of pBIN1.","authors":"Qian-Jin Guo, Jing-Hui Liang, Hong-Tao Li, Lin-Lin Li, Yingna Guo, Li-Peng Wang, Xin-Lei Ma, Xian-Jin Xie, Tingting Hou, Shi-Qiang Wang","doi":"10.1161/CIRCRESAHA.124.325472","DOIUrl":"10.1161/CIRCRESAHA.124.325472","url":null,"abstract":"<p><strong>Background: </strong>Transverse tubules (TTs) are tubular invaginations of myocyte membrane forming junctions with sarcoplasmic reticulum and are essential for excitation-contraction coupling. Although it is known that TTs begin to develop 2 weeks after birth in rodent cardiomyocytes, the spatial profile and molecular mechanisms of TT morphogenesis are not clear. Understanding the molecular mechanism of TT morphogenesis may provide potential solutions for TT loss in pathogenic conditions such as hypertrophy and heart failure.</p><p><strong>Methods: </strong>To understand early stage morphogenesis of cardiac TTs, we utilized a scanning electron microscope equipped with a focused ion beam to reconstruct a 3-dimensional spatial profile of developing TT network in cardiomyocytes from 2-week-old rats. We created tamoxifen-inducible cardiac-specific knockout rats to explore the role of exons 11 and 13 of the <i>BIN1</i> (bridging integrator 1) gene.</p><p><strong>Results: </strong>We found that TTs began to develop as intracellular membrane hubs around Z-discs, from which pseudopod-like tubules budded in a relatively random way toward different directions without necessarily connecting to the cell surface. A tubule network forms when membrane branches from adjacent hubs are interconnected. Cardiac-specific knockout of <i>BIN1</i> exon 13 (13KO) suppressed TT microfolds. In contrast, cardiac-specific knockout of <i>BIN1</i> exon 11 (11KO), which encodes the PIBM (phosphoinositide-binding motif), suppressed the formation of budding tubules, resulting in a sparse tubule network with swollen membrane hubs. Due to the underdeveloped TT network, TT-sarcoplasmic reticulum couplon density/size and excitation-contraction coupling gain in 11KO cardiomyocytes were decreased, similar to those occurring in failing heart cells.</p><p><strong>Conclusions: </strong>TTs start to develop as budding tubules branching from membrane hubs around Z-discs. This process depends at least partially on the tubulation function of pBIN1 (BIN1 isoforms with PIBM [Bin1+11 and Bin1+11+17]), which is constitutively expressed in rat and human cardiomyocytes. Defective TT morphogenesis due to altered <i>BIN1</i> splicing in cardiomyocytes may have potential implications in heart diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"435-448"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282709","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: Multiorgan Imaging for Interorgan Crosstalk in Cardiometabolic Diseases.","authors":"Ana Devesa, Victoria Delgado, Ladislav Valkovic, Joao A C Lima, Eike Nagel, Borja Ibanez, Betty Raman","doi":"10.1161/RES.0000000000000722","DOIUrl":"https://doi.org/10.1161/RES.0000000000000722","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 3","pages":"e62"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658584","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":"Super-Enhancer-Driven HCG20 Promotes Pulmonary Hypertension Through U2AF2 Splicing.","authors":"Jian Mei, Wei Huang, Zitong Meng, Shiqing Wen, Langlin Ou, June Bai, Xiaoying Wang, Hao Yuan, Yanyu Li, Lixin Zhang, Yuwei You, Yingli Chen, Xiaodong Zheng, Fei Li, Song Wang, Xiangrui Zhu, Zhaosi Wang, Daling Zhu, Xiaowei Nie, Cui Ma","doi":"10.1161/CIRCRESAHA.125.326133","DOIUrl":"10.1161/CIRCRESAHA.125.326133","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pulmonary artery endothelial cell (PAEC) dysfunction is a pathological hallmark of pulmonary hypertension (PH). Yet, the roles of long noncoding RNAs (lncRNAs) driven by super-enhancers (SEs) in PAECs are not well understood. In this study, we focused on the PAEC-specific SE-associated lncRNA HCG20 (HLA complex group 20) and to elucidate its role and underlying mechanisms in the progression of PH.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), chromosome conformation capture followed by PCR , CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), and dual-luciferase reporter assays were used to identify dysregulated SE-associated lncRNAs in PAECs and to investigate the pathological role of HCG20. The role of HCG20 in pathological processes was validated in rodent models of PH induced by SU5416/hypoxia, monocrotaline, or hypoxia alone, through adeno-associated virus-mediated endothelial-specific HCG20 overexpression or knockdown of HCG20. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and RNA sequencing were used to elucidate the underlying mechanisms of HCG20-mediated PAEC dysfunction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We identified the SE-associated lncRNA HCG20 from histone H3 lysine-27 acetylation (H3K27ac) and histone H3 lysine-4 monomethylation (H3K4me1) chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) data derived from PAECs of patients with PH. A significant upregulation of HCG20 was found in hypoxia-induced human PAECs, lung tissues, and the plasma of patients with PH. Antisense oligonucleotide and CRISPR/Cas9, which, respectively, target HCG20 and its SE, alleviate hypoxia-induced pyroptosis and subsequent endothelial-to-mesenchymal transition. Human pulmonary artery smooth muscle cells internalize human PAEC-derived exosomes containing HCG20, inducing their excessive proliferation. Targeted delivery of HCG20 into the pulmonary vascular endothelium induced pulmonary vasculature remodeling and increased pulmonary artery systolic blood pressure in rodents. Mechanistically, HCG20 directly bound and stabilized the U2AF2 (U2 small nuclear RNA auxiliary factor 2) protein, thereby facilitating its impact on the alternative splicing of EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2). Furthermore, we identified a novel mouse ortholog gene, 4833427F10Rik (named Hcg20), of HCG20 for the first time. Our study demonstrated that specific interference with Hcg20 in the pulmonary vascular intima has been shown to ameliorate hypoxia-induced PH.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Collectively, our data suggest that HCG20, driven by SE, contributes to PAEC dysfunction through U2AF2-mediated alternative splicing of EIF2AK2. Our work underscores the potential of using HCG20 as a novel biomarker and a promising target for th","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e19-e39"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157203","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":"cDC1s Promote Atherosclerosis via Local Immunity and Are Targetable for Therapy.","authors":"Miguel Galán, Laura Fernández-Méndez, Vanessa Núñez, Marcos Femenía-Muiña, Pau Figuera-Belmonte, Elena Moya-Ruiz, Sarai Martínez-Cano, Elena Hernández-García, Manuel Rodrigo-Tapias, Ana Rodríguez-Ronchel, Carlos Relaño-Rupérez, Stefanie K Wculek, Alberto Benguria, Ana Dopazo, Sandrine Henri, Suin Jo, Tian-Tian Liu, Bernard Malissen, Kenneth M Murphy, Almudena R Ramiro, Susana Carregal-Romero, Jesús Ruiz-Cabello, Iñaki Robles-Vera, David Sancho","doi":"10.1161/CIRCRESAHA.124.325792","DOIUrl":"10.1161/CIRCRESAHA.124.325792","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is characterized by immune cell accumulation in the arterial wall and adaptive CD4⁺ T helper 1 immunity contributes to atherosclerosis development. However, how conventional dendritic cells (DCs) orchestrate this adaptive response remains controversial. This study unveils strategies for the gain and loss of function of cDCs to decipher their role in atherosclerosis induction in relation to adaptive T-cell immunity.</p><p><strong>Methods: </strong>We tested atherosclerosis in <i>Ldlr</i>^-/- mice fed a high-cholesterol diet (HCD). Expansion of DCs in vivo was achieved by overexpression of FLT3L (Fms-like tyrosine kinase 3 ligand), while the effect of ablation of conventional type 1 DCs (cDC1s) in atherosclerosis was analyzed by grafting bone marrow from different mouse models of cDC1 depletion, including <i>Xcr1</i>^Cre-DTA and <i>Irf8</i>Δ32 mice, into lethally irradiated <i>Ldlr</i>^-/- recipients before HCD. CD3⁺ T-cell subsets were analyzed using flow cytometry or single-cell RNA sequencing (scRNA-seq). Nanoparticles loaded with dexamethasone and decorated with anti-CLEC9A antibody to target cDC1s were tested for immunotherapy.</p><p><strong>Results: </strong>Expansion of DCs in <i>Ldlr</i>^-<i>/</i>- mice fed HCD for 8 weeks led to increased atherosclerotic lesion, which was prevented when <i>Ldlr</i>^-<i>/</i>- mice were grafted before DC expansion with <i>Xcr1</i>^Cre-DTA cDC1-depleted bone marrow compared with controls. Consistently, even in the absence of DC expansion, cDC1 deficiency prevented HCD-induced atherosclerosis. The scRNA-seq analysis of aortic CD3⁺ T cells in this experimental approach showed a local reduction in CD4⁺ Th1 and CD8⁺ IFN (interferon)-γ⁺ T cells in the absence of cDC1s compared with control mice. Mechanistically, stimulator of IFN genes (STING) in cDC1s was required for the proatherogenic function of cDC1s. As a potential cDC1-targeted immunotherapy for atherosclerosis, we generated lipid nanoparticles decorated with an anti-CLEC9A antibody to specifically target cDC1s. When loaded with the immunosuppressive drug dexamethasone, these nanoparticles promoted a reduction of the atherosclerotic lesion in <i>Ldlr</i>^-<i>/</i>- mice fed HCD, correlating with decreased CD4⁺ Th1 and CD8⁺ IFN-γ⁺ T cells in the spleen. These immunosuppressive nanoparticles, however, did not impair antiviral response.</p><p><strong>Conclusions: </strong>Using state-of-the-art strategies, our results establish that cDC1s have a proatherogenic role in atherosclerosis by boosting CD4⁺ and CD8⁺ T-cell immunity and propose that cDC1s can be targeted with an immunosuppressive drug to decrease atherosclerosis progression.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"400-416"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179995","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":"Disturbed Repolarization-Relaxation Coupling During Acute Myocardial Ischemia Permits Systolic Mechano-Arrhythmogenesis.","authors":"Breanne A Cameron, Peter A Baumeister, Tarek Lawen, Sara A Rafferty, Behzad Taeb, Matthew R Stoyek, Joachim Greiner, Ilija Uzelac, Flavio H Fenton, Rémi Peyronnet, Peter Kohl, T Alexander Quinn","doi":"10.1161/CIRCRESAHA.124.326057","DOIUrl":"10.1161/CIRCRESAHA.124.326057","url":null,"abstract":"<p><strong>Background: </strong>The heart's mechanical state feeds back to its electrical activity, potentially contributing to arrhythmias. Mechano-arrhythmogenesis has been mechanistically explained during electrical diastole, when cardiomyocytes are at their resting membrane potential. During electrical systole, cardiomyocytes are refractory right after the onset of depolarization, while during repolarization in physiological conditions, they seem to be protected from systolic mechano-arrhythmogenesis by near-simultaneous restoration of resting membrane potential and cytosolic calcium concentration ([Ca²⁺]_i): repolarization-relaxation coupling (RRC). Yet, late-systolic mechano-arrhythmogenesis has been reported in ischemic myocardium, with unclear underlying mechanisms. We hypothesize that ischemia-induced alteration of RRC gives rise to a vulnerable period for mechano-arrhythmogenesis.</p><p><strong>Methods: </strong>Acute left ventricular regional ischemia was induced by coronary artery ligation in Langendorff-perfused rabbit hearts, with mechanical load controlled by an intraventricular balloon. Mechanical activity was assessed by echocardiography and arrhythmia incidence by ECG. Single left ventricular cardiomyocytes were exposed to simulated ischemia or pinacidil (ATP-sensitive potassium channel opener). Stretch was applied in diastole or late systole using carbon fibers. Stretch characteristics and arrhythmia incidence were assessed by sarcomere length measurement. In both models, RRC was assessed by simultaneous voltage-[Ca²⁺]_i fluorescence imaging and mechano-arrhythmogenesis mechanisms were pharmacologically tested.</p><p><strong>Results: </strong>In whole hearts, acute regional ischemia leads to systolic stretch and disturbed RRC at the ischemic border. These electro-mechanical changes were associated with waves of arrhythmias, which could be reduced by mechanical unloading, electro-mechanical uncoupling, or buffering of [Ca²⁺]_i. In left ventricular cardiomyocytes, physiological RRC is associated with a low incidence of systolic mechano-arrhythmogenesis, while a vulnerable period emerged by prolonged RRC during ischemia. The increase in systolic mechano-arrhythmogenesis was reduced by restoring RRC, chelating [Ca²⁺]_i, blocking mechano-sensitive TRPA1 (transient receptor potential ankyrin 1) channels, or buffering reactive oxygen species levels.</p><p><strong>Conclusions: </strong>Prolonged RRC allows for late-systolic mechano-arrhythmogenesis in acute ischemia, involving contributions of elevated [Ca²⁺]_i, TRPA1 activity, and reactive oxygen species, which represent potential antiarrhythmic targets.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"363-382"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198378","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000725","DOIUrl":"https://doi.org/10.1161/RES.0000000000000725","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"137 3","pages":"361-362"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658585","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":"RCAN1-Mediated Calcineurin Impairment Drives Sympathetic Outflow in Hypertension.","authors":"Jing-Jing Zhou, Jian-Ying Shao, Shao-Rui Chen, Zeng-You Ye, Hui-Lin Pan","doi":"10.1161/CIRCRESAHA.124.325975","DOIUrl":"10.1161/CIRCRESAHA.124.325975","url":null,"abstract":"<p><strong>Background: </strong>Calcineurin activity in the hypothalamic paraventricular nucleus (PVN) constitutively suppresses sympathetic output by tonically inhibiting glutamate NMDARs (<i>N</i>-methyl-D-aspartate receptors). Clinically used calcineurin inhibitors diminish calcineurin activity in the PVN, leading to persistent overactivation of the sympathetic nervous system. In this study, we investigated the role of calcineurin signaling in the PVN in sympathetic overactivity in spontaneously hypertensive rats (SHR), a widely used genetic model for essential hypertension.</p><p><strong>Methods: </strong>Arterial blood pressure in conscious animals was recorded via radiotelemetry. Protein-protein interactions were assessed using coimmunoprecipitation, and synaptic NMDAR activity was measured using whole-cell patch-clamp recordings.</p><p><strong>Results: </strong>Calcineurin phosphatase activity in the PVN and other forebrain regions was much lower in SHR than in normotensive Wistar-Kyoto rats (WKY). However, systemic treatment with angiotensin II had no significant effect on brain calcineurin activity. Systemic administration of tacrolimus (FK506), a specific calcineurin inhibitor, induced persistent hypertension in WKY but did not affect the already elevated blood pressure in SHR. Also, microinjection of FK506 into the PVN significantly increased renal sympathetic nerve activity and blood pressure in WKY but had no effect on SHR. Furthermore, FK506 treatment increased α2δ-1-NMDAR interactions and synaptic NMDAR activity in spinally projecting PVN neurons in WKY but not in SHR. Blocking NMDARs with memantine or inhibiting α2δ-1 with gabapentin substantially reduced elevated blood pressure in both FK506-treated WKY and SHR. Despite comparable levels of calcineurin-NMDAR complexes in the PVN of WKY and SHR, the interaction between calcineurin and RCAN1 (regulator of calcineurin 1, also known as calcipressin-1 or DSCR1 [Down syndrome critical region 1]), an endogenous calcineurin inhibitor, was significantly increased in SHR. Serine phosphorylation of RCAN1.1L in the PVN was much greater in SHR than in WKY. Disrupting RCAN1-calcineurin interactions using an RCAN1 C terminus peptide reversed synaptic NMDAR hyperactivity in spinally projecting PVN neurons in SHR. In addition, microinjection of the RCAN1 C terminus peptide into the PVN attenuated renal sympathetic nerve activity and arterial blood pressure in SHR.</p><p><strong>Conclusions: </strong>RCAN1-mediated calcineurin hypoactivity in the PVN augments sympathetic outflow by promoting synaptic expression and activity of α2δ-1-bound NMDARs in SHR. These findings identify a novel molecular mechanism underlying sympathetic overactivity in genetic hypertension and suggest potential therapeutic targets for neurogenic hypertension.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"417-434"},"PeriodicalIF":16.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282710","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: 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}