Circulation最新文献

{"title":"Activation of Imprinted Gene <i>PW1</i> Promotes Cardiac Fibrosis After Ischemic Injury.","authors":"Shan Kou, Zhengkai Lu, Defang Deng, Min Ye, Yu Sui, Lieyang Qin, Teng Feng, Zhen Jiang, Jufeng Meng, Chao-Po Lin, Xiajun Li, Chen Liu, Juan Tang, Hui Zhang","doi":"10.1161/CIRCULATIONAHA.124.070738","DOIUrl":"10.1161/CIRCULATIONAHA.124.070738","url":null,"abstract":"<p><strong>Background: </strong>Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition in the myocardium, is an important target for heart disease treatments. <i>Pw1</i> (paternally expressed gene 3) is an imprinted gene expressed from the paternal allele, and de novo purine biosynthesis (DNPB) is a crucial pathway for nucleotide synthesis. However, the roles of PW1 and DNPB in ECM production by cardiac fibroblasts during myocardial ischemia are not yet understood.</p><p><strong>Methods: </strong>To induce myocardial damage, we performed left anterior descending coronary artery ligation. We generated <i>Pw1</i>^{<i>CreER-2A-eGFP</i>} and <i>Pw1</i>^{<i>2A-CreER</i>} knock-in mouse lines to evaluate the expression of the 2 <i>Pw1</i> alleles in normal and injured hearts. Bisulfite sequencing was used to analyze the DNA methylation of the <i>Pw1</i> imprinting control region. We identified the phosphoribosylformylglycinamidine synthase (<i>Pfas</i>) gene, encoding the DNPB enzyme PFAS, as a direct target of PW1 using chromatin immunoprecipitation sequencing and real-time quantitative polymerase chain reaction. The role of DNPB in ECM production and cardiac fibrosis after injury was examined in vitro using cultured cardiac fibroblasts and in vivo with <i>Pfas</i>-deficient mice.</p><p><strong>Results: </strong>Our study demonstrates that myocardial infarction reduces DNA methylation at the imprinting control region of the maternally imprinted gene <i>Pw1</i>, triggering a switch from monoallelic imprinting to biallelic expression of <i>Pw1</i> in cardiac fibroblasts. In activated cardiac fibroblasts, increased <i>Pw1</i> expression promotes purine biosynthesis and induces ECM production by transcriptionally activating the DNPB factor <i>Pfas</i>. We identified that DNPB is essential for ECM production in activated fibroblasts and that loss of <i>Pfas</i> in fibroblasts limits cardiac fibrosis and improves heart function after injury.</p><p><strong>Conclusions: </strong>This study demonstrates that <i>Pw1</i> imprinting is disrupted after injury and reveals a novel role for the downstream target PFAS in ECM production and cardiac fibrogenesis. Targeting the PW1/PFAS signaling pathway presents a promising therapeutic strategy for improving cardiac repair after injury.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"623-639"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863546","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":"Decoding <i>Pw1</i> Imprinting in the Postischemic Heart: A Novel Antifibrotic Strategy?","authors":"Thomas A Agbaedeng","doi":"10.1161/CIRCULATIONAHA.125.073505","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.125.073505","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 9","pages":"640-643"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604097","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":"Response by Guo et al to Letter Regarding Article, \"LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p\".","authors":"Xiao Guo, Ji Gao, Jun Pu","doi":"10.1161/CIRCULATIONAHA.124.072687","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072687","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 9","pages":"e684-e685"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604108","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":"Targeting uPARAP Modifies Lymphatic Vessel Architecture and Attenuates Lymphedema.","authors":"Fabrice Gucciardo, Alizée Lebeau, Sébastien Pirson, Florence Buntinx, Elitsa Ivanova, Silvia Blacher, Pascal Brouillard, Jonathan Deroye, Louis Baudin, Alexandra Pirnay, Florent Morfoisse, Claire Villette, Christophe Nizet, François Lallemand, Carine Munaut, Kari Alitalo, Liesbet Geris, Miikka Vikkula, Marine Gautier-Isola, Agnès Noel","doi":"10.1161/CIRCULATIONAHA.124.072093","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072093","url":null,"abstract":"<p><strong>Background: </strong>Lymphedema is an incurable disease associated with lymphatic dysfunction that causes tissue swelling and fibrosis. We investigated whether lymphedema could be attenuated by interfering with uPARAP (urokinase plasminogen activator receptor-associated protein; <i>Mrc2</i> gene), an endocytic receptor involved in fibrosis and lymphangiogenesis.</p><p><strong>Methods: </strong>We generated mice with lymphatic endothelial cell (LEC)-specific <i>uPARAP</i> deficiency and compared them with constitutive knockout mice by applying a preclinical model of secondary lymphedema (SL). Computerized methods were applied for 2-dimensional and 3-dimensional image quantifications. Cellular effects of uPARAP deletion on lymphatic permeability were assessed by small interfering RNA-mediated silencing in human dermal LECs and a pharmacologic treatment targeting ROCK (rho-associated coiled coil containing kinase), an established regulator of cell junctions. The uPARAP and vascular endothelial cadherin partnership was investigated through proximity ligation assay, coimmunoprecipitation, and immunostaining. An in silico model was generated to analyze the fluid-absorbing function of the lymphatic vasculature. To interfere with uPARAP, its downregulation was achieved in vivo through a gapmer approach.</p><p><strong>Results: </strong>uPARAP deficiency mitigated several key pathologic features of SL, including hindlimb swelling, epidermal thickening, and the accumulation and size of adipocytes. In both global and LEC-conditional uPARAP-deficient mice, induction of SL led to a distinctive labyrinthine vasculature, defined herein by twisted and hyperbranched vessels with overlapping cells. This topology, mainly composed of pre-collecting vessels, correlated with reduced SL, but not with change in fibrosis, highlighting the importance of uPARAP in regulating LEC functions in a lymphedematous context. In vitro, <i>uPARAP</i> knockdown in LECs impaired vascular endothelial growth factor C-mediated endosomal trafficking of vascular endothelial cadherin and induced overlapping cell junctions. The pharmacologic inhibition of ROCK recapitulated cell superimposition in vitro and the labyrinthine vasculature in vivo with attenuated SL. Computational modeling of labyrinthine lymphatic vasculature supported the observation on their improved fluid-absorbing function in comparison with a normal hierarchic network. These data provide proof of concept of inducing a labyrinthine topology to treat SL. For therapeutic purposes, we validated the use of an anti-uPARAP gapmer to induce a labyrinthine vasculature and attenuate SL formation.</p><p><strong>Conclusions: </strong>Our findings provide evidence that downregulating uPARAP expression can induce a beneficial remodeling of lymphatic vasculature that attenuates lymphedema through a cell junction-based mechanism, offering a novel therapeutic pathway for lymphedema.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":""},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539431","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":"Heart Failure: A Century View, From Failure to Function.","authors":"Clyde W Yancy","doi":"10.1161/CIRCULATIONAHA.124.072249","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.072249","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 9","pages":"585-588"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604101","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":"Letter by Teng et al Regarding Article, \"LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p\".","authors":"Zhenqing Teng, Like Ma, Xiang Ma","doi":"10.1161/CIRCULATIONAHA.124.070481","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070481","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 9","pages":"e682-e683"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604103","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":"Stepwise Provisional Versus Systematic Dual-Stent Strategies for Treatment of True Left Main Coronary Bifurcation Lesions.","authors":"Sandeep Arunothayaraj, Mohaned Egred, Adrian P Banning, Philippe Brunel, Miroslaw Ferenc, Thomas Hovasse, Adrian Wlodarczak, Manuel Pan, Thomas Schmitz, Marc Silvestri, Andreis Erglis, Evgeny Kretov, Jens Flensted Lassen, Alaide Chieffo, Thierry Lefèvre, Francesco Burzotta, James Cockburn, Olivier Darremont, Goran Stankovic, Marie-Claude Morice, Yves Louvard, David Hildick-Smith","doi":"10.1161/CIRCULATIONAHA.124.071153","DOIUrl":"10.1161/CIRCULATIONAHA.124.071153","url":null,"abstract":"<p><strong>Background: </strong>The optimal coronary stenting technique for true left main bifurcation lesions is uncertain. EBC MAIN (European Bifurcation Club Left Main Trial) aimed to evaluate clinical outcomes of a stepwise provisional strategy compared with a systematic dual-stent approach.</p><p><strong>Methods: </strong>EBC MAIN was a randomized, investigator-initiated, open-label, multicenter, parallel-group trial conducted across 35 hospitals in 11 European countries. A total of 467 participants undergoing percutaneous coronary intervention for unprotected true left main bifurcation lesions were randomly assigned to the stepwise provisional strategy (n=230) or an upfront dual-stent approach (n=237). The mean (SD) age was 71 (10) years and 23% of participants were women. The primary end point was a composite of major adverse cardiac events, defined as all-cause mortality, all myocardial infarction, or clinically driven target lesion revascularization. Events were adjudicated by an independent clinical events committee and all analyses were by the intention-to-treat principle.</p><p><strong>Results: </strong>At 3 years, the primary end point occurred in 54 of 230 (23.5%) stepwise provisional and 70 of 237 (29.5%) dual-stent patients (hazard ratio, 0.75 [95% CI, 0.53-1.07]; <i>P</i>=0.11). There was no significant difference in all-cause mortality (10.0% versus 13.1%) or myocardial infarction (12.2% versus 11.0%). However, target lesion revascularization was significantly lower in the stepwise provisional group (8.3% versus 15.6%; hazard ratio, 0.50 [95% CI, 0.29-0.86]; <i>P</i>=0.013). In this population, the mean side vessel diameter by quantitative angiography was 2.9 mm, and median side vessel lesion length was 5 mm. Significant interactions were identified between the assigned bifurcation strategy and both side vessel diameter and lesion length with respect to the primary outcome (<i>P</i>=0.009 and <i>P</i>=0.005, respectively), with smaller vessels (<3.25 mm diameter) and shorter lesions (<10 mm length) favoring the provisional approach.</p><p><strong>Conclusions: </strong>In a European population with true left main stem bifurcation coronary disease requiring intervention, there was no difference in major adverse cardiovascular events between stepwise provisional and systematic dual-stent strategies at 3 years. Target lesion revascularization was significantly less frequent with the stepwise provisional approach, which should be the default strategy for noncomplex left main bifurcation coronary intervention.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02497014.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"612-622"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188586","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":"Prevalence of Lipoprotein(a) Testing in a Contemporary Cohort.","authors":"Agam Bansal, Leslie Cho","doi":"10.1161/CIRCULATIONAHA.124.070361","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.070361","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 9","pages":"649-651"},"PeriodicalIF":35.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604105","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":"S100A1ct: A Synthetic Peptide Derived From S100A1 Protein Improves Cardiac Performance and Survival in Preclinical Heart Failure Models.","authors":"Dorothea Kehr, Julia Ritterhoff, Manuel Glaser, Lukas Jarosch, Rafael E Salazar, Kristin Spaich, Karl Varadi, Jennifer Birkenstock, Michael Egger, Erhe Gao, Walter J Koch, Max Sauter, Marc Freichel, Hugo A Katus, Norbert Frey, Andreas Jungmann, Cornelius Busch, Paul J Mather, Arjang Ruhparwar, Martin Busch, Mirko Völkers, Rebecca C Wade, Patrick Most","doi":"10.1161/CIRCULATIONAHA.123.066961","DOIUrl":"10.1161/CIRCULATIONAHA.123.066961","url":null,"abstract":"<p><strong>Background: </strong>The EF-hand Ca²⁺ sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. The ability of S100A1 to recognize and modulate the activity of targets such as SERCA2a (sarcoplasmic reticulum Ca²⁺ ATPase) and RyR2 (ryanodine receptor 2) in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminal α-helix (residues 75-94). We hypothesized that a synthetic peptide consisting of residues 75 through 94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance-enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts.</p><p><strong>Methods: </strong>We applied an integrative translational research pipeline ranging from in silico computational molecular modeling and in vitro biochemical molecular assays as well as isolated rodent and human cardiomyocyte performance assessments to in vivo safety and efficacy studies in small and large animal cardiac disease models.</p><p><strong>Results: </strong>We characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardium in vitro and in vivo. This activity translates into improved contractile performance and survival in preclinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca²⁺ cycling and prevents β-adrenergic receptor-triggered Ca²⁺ imbalances by targeting SERCA2a and RyR2 activity. In line with the S100A1ct-mediated enhancement of SERCA2a activity, modeling suggests an interaction of the peptide with the transmembrane segments of the sarcoplasmic Ca²⁺ pump. Incorporation of a cardiomyocyte-targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potency in vitro and in vivo.</p><p><strong>Conclusions: </strong>S100A1ct is a promising lead for the development of novel peptide-based therapeutics against heart failure with reduced ejection fraction.</p>","PeriodicalId":10331,"journal":{"name":"Circulation","volume":" ","pages":"548-565"},"PeriodicalIF":35.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680976","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":"Coronary CT Anatomy-Based Prediction of Invasively Assessed Hemodynamic Significance in Middle-Aged Patients With Right Coronary Artery Anomaly: The NARCO Study.","authors":"Anselm W Stark, René L Matthey-de-l'Endroit, Adriana Ferroni, Ryota Kakizaki, Marius R Bigler, Flavio G Biccirè, Yasushi Ueki, Andreas Haeberlin, Matthias Siepe, Isaac Shiri, Stephan Windecker, Lorenz Räber, Christoph Gräni","doi":"10.1161/CIRCULATIONAHA.124.071637","DOIUrl":"https://doi.org/10.1161/CIRCULATIONAHA.124.071637","url":null,"abstract":"","PeriodicalId":10331,"journal":{"name":"Circulation","volume":"151 8","pages":"578-580"},"PeriodicalIF":35.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491027","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}