Circulation research最新文献

{"title":"Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.","authors":"Jonathan D Hoang, Valerie Y H van Weperen, Ki-Woon Kang, Neil R Jani, Mohammed A Swid, Christopher A Chan, Zulfiqar Ali Lokhandwala, Robert L Lux, Marmar Vaseghi","doi":"10.1161/CIRCRESAHA.123.324058","DOIUrl":"10.1161/CIRCRESAHA.123.324058","url":null,"abstract":"<p><strong>Background: </strong>Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction.</p><p><strong>Methods: </strong>Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (S_max) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation.</p><p><strong>Results: </strong>TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and S_max was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity.</p><p><strong>Conclusions: </strong>TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in S_max, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e57-e75"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466571","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":"Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.","authors":"Yoshinobu Nakayama, Satoru Kobayashi, Aliya Masihuddin, Syed Amir Abdali, A M Pramodh Bandara Seneviratne, Sachiyo Ishii, Jun Iida, Qiangrong Liang, Jun Yoshioka","doi":"10.1161/CIRCRESAHA.123.323158","DOIUrl":"10.1161/CIRCRESAHA.123.323158","url":null,"abstract":"<p><strong>Background: </strong>Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.</p><p><strong>Methods: </strong>To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models.</p><p><strong>Results: </strong>High glucose promoted translocation of MondoA into the nucleus, which upregulated <i>Arrdc4</i> transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of <i>ARRDC4</i> was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial <i>Arrdc4</i> expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of <i>Arrdc4</i> augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that <i>Arrdc4</i>-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial <i>ARRDC4</i> have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the <i>ARRDC4</i> mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.</p><p><strong>Conclusions: </strong>ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"416-433"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466572","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.0000000000000683","DOIUrl":"https://doi.org/10.1161/RES.0000000000000683","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 3","pages":"414-415"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723177","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":"Therapeutic Inhibition of <i>LincRNA-p21</i> Protects Against Cardiac Hypertrophy.","authors":"Yi Wang, Mingming Zhang, Rong Wang, Jing Lin, Qing Ma, Haipeng Guo, Huihui Huang, Zhuomin Liang, Yangpo Cao, Xiaoran Zhang, Yao Wei Lu, Jianming Liu, Feng Xiao, Hualin Yan, Nadya Dimitrova, Zhan-Peng Huang, John D Mably, William T Pu, Da-Zhi Wang","doi":"10.1161/CIRCRESAHA.123.323356","DOIUrl":"10.1161/CIRCRESAHA.123.323356","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood.</p><p><strong>Methods: </strong>We measured <i>lincRNA-p21</i> RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of <i>lincRNA-p21</i> in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of <i>lincRNA-p21</i> inhibition in cardiac hypertrophy and associated heart failure.</p><p><strong>Results: </strong><i>lincRNA-p21</i> was induced in mice and humans with cardiomyopathy. Global and cardiac-specific <i>lincRNA-p21</i> knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that <i>lincRNA-p21</i> acts <i>in trans</i> to stimulate the NFAT/MEF2 (nuclear factor of activated T cells/myocyte enhancer factor-2) pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1 (KRAB-associated protein-1). <i>lincRNA-p21</i> cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting <i>lincRNA-p21</i>.</p><p><strong>Conclusions: </strong>These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of <i>lincRNA-p21</i> as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"434-449"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305551","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":"Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart.","authors":"Claudio Humeres, Arti V Shinde, Izabela Tuleta, Silvia C Hernandez, Anis Hanna, Shuaibo Huang, Harikrishnan Venugopal, Jennifer T Aguilan, Simon J Conway, Simone Sidoli, Nikolaos G Frangogiannis","doi":"10.1161/CIRCRESAHA.123.323360","DOIUrl":"10.1161/CIRCRESAHA.123.323360","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cardiac fibroblast activation contributes to adverse remodeling, fibrosis, and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β (transforming growth factor-β)/Smad (small mother against decapentaplegic)-3 activation protects the pressure-overloaded heart by preserving the matrix, sustained TGF-β activation is deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF-β response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. We hypothesized that Smad7, an inhibitory Smad that restrains TGF-β signaling, may be induced in the pressure-overloaded myocardium and may regulate fibrosis, remodeling, and dysfunction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The effects of myofibroblast-specific Smad7 loss were studied in a mouse model of transverse aortic constriction, using echocardiography, histological analysis, and molecular analysis. Proteomic studies in S7KO (Smad7 knockout) and overexpressing cells were used to identify fibroblast-derived mediators modulated by Smad7. In vitro experiments using cultured cardiac fibroblasts, fibroblasts populating collagen lattices, and isolated macrophages were used to dissect the molecular signals responsible for the effects of Smad7.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Following pressure overload, Smad7 was upregulated in cardiac myofibroblasts. TGF-β and angiotensin II stimulated fibroblast Smad7 upregulation via Smad3, whereas GDF15 (growth differentiation factor 15) induced Smad7 through GFRAL (glial cell line-derived neurotrophic factor family receptor α-like). MFS7KO (myofibroblast-specific S7KO) mice had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to transverse aortic constriction. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased MMP (matrix metalloproteinase)-2 activity and collagen denaturation. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins and markedly increases MMP2 secretion. In contrast, Smad7 overexpression reduced MMP2 levels. In fibroblasts populating collagen lattices, the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Macrophage activation involved the combined effects of the fibroblast-derived matricellular proteins CD5L (CD5 antigen-like), SPARC (secreted protein acidic and rich in cysteine), CTGF (connective tissue growth factor), ECM1 (extracellular matrix protein 1), and TGFBI (TGFB induced).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The antifibrotic effects of Smad7 in the pressure-over","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"453-469"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426428","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":"CD163⁺ Macrophages Induce Endothelial-to-Mesenchymal Transition in Atheroma.","authors":"Masayuki Mori, Atsushi Sakamoto, Rika Kawakami, Liang Guo, Lotte Slenders, Jose Verdezoto Mosquera, Saikat Kumar B Ghosh, Marian Wesseling, Tatsuya Shiraki, Arielle Bellissard, Palak Shah, Craig C Weinkauf, Takao Konishi, Yu Sato, Anne Cornelissen, Kenji Kawai, Hiroyuki Jinnouchi, Weili Xu, Aimee E Vozenilek, Desiree Williams, Takamasa Tanaka, Teruo Sekimoto, Michael C Kelly, Raquel Fernandez, Alyssa Grogan, A J Coslet, Alisa Fedotova, Anjali Kurse, Michal Mokry, Maria E Romero, Frank D Kolodgie, Gerard Pasterkamp, Clint L Miller, Renu Virmani, Aloke V Finn","doi":"10.1161/CIRCRESAHA.123.324082","DOIUrl":"10.1161/CIRCRESAHA.123.324082","url":null,"abstract":"<p><strong>Background: </strong>Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163⁺ macrophages. Here, we explored the hypothesis that CD163⁺ macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap.</p><p><strong>Methods: </strong>Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone <i>ApoE</i>^<i>-/-</i> and <i>ApoE</i>^<i>-/-</i><i>/CD163</i>^<i>-/-</i> mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments.</p><p><strong>Results: </strong>In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163⁺ macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163⁺ macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163⁺ macrophage-induced EndMT. Additionally, <i>CD163</i> deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes.</p><p><strong>Conclusions: </strong>CD163⁺ macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e4-e23"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300156","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":"Clinical Characteristics and Mechanisms of Acute Myocarditis.","authors":"Stephane Heymans, Sophie Van Linthout, Sarah Mignon Kraus, Leslie T Cooper, Ntobeko A B Ntusi","doi":"10.1161/CIRCRESAHA.124.324674","DOIUrl":"10.1161/CIRCRESAHA.124.324674","url":null,"abstract":"<p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT05335928.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"397-411"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533739","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":"Combined Lipid Disturbances: More Than the Sum of Their Parts?","authors":"Robert A Hegele","doi":"10.1161/CIRCRESAHA.124.324793","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.324793","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 2","pages":"277-279"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533740","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":"TRIM35 Monoubiquitinates H2B in Cardiac Cells, Implications for Heart Failure.","authors":"Maria Areli Lorenzana-Carrillo, Saymon Tejay, Joseph Nanoa, Guocheng Huang, Yongsheng Liu, Alois Haromy, Yuan Yuan Zhao, Michelle Mendiola Pla, Dawn E Bowles, Adam Kinnaird, Evangelos D Michelakis, Gopinath Sutendra","doi":"10.1161/CIRCRESAHA.123.324202","DOIUrl":"10.1161/CIRCRESAHA.123.324202","url":null,"abstract":"<p><strong>Background: </strong>The tumor suppressor and proapoptotic transcription factor P53 is induced (and activated) in several forms of heart failure, including cardiotoxicity and dilated cardiomyopathy; however, the precise mechanism that coordinates its induction with accessibility to its transcriptional promoter sites remains unresolved, especially in the setting of mature terminally differentiated (nonreplicative) cardiomyocytes.</p><p><strong>Methods: </strong>Male and female control or TRIM35 (tripartite motif containing 35) overexpression adolescent (aged 1-3 months) and adult (aged 4-6 months) transgenic mice were used for all in vivo experiments. Primary adolescent or adult mouse cardiomyocytes were isolated from control or TRIM35 overexpression transgenic mice for all in vitro experiments. Adenovirus or small-interfering RNA was used for all molecular experiments to overexpress or knockdown, respectively, target genes in primary mouse cardiomyocytes. Patient dilated cardiomyopathy or nonfailing left ventricle samples were used for translational and mechanistic insight. Chromatin immunoprecipitation and DNA sequencing or quantitative real-time polymerase chain reaction (qPCR) was used to assess P53 binding to its transcriptional promoter targets, and RNA sequencing was used to identify disease-specific signaling pathways.</p><p><strong>Results: </strong>Here, we show that E3-ubiquitin ligase TRIM35 can directly monoubiquitinate lysine-120 (K120) on histone 2B in postnatal mature cardiomyocytes. This epigenetic modification was sufficient to promote chromatin remodeling, accessibility of P53 to its transcriptional promoter targets, and elongation of its transcribed mRNA. We found that increased P53 transcriptional activity (in cardiomyocyte-specific <i>Trim35</i> overexpression transgenic mice) was sufficient to initiate heart failure and these molecular findings were recapitulated in nonischemic human LV dilated cardiomyopathy samples.</p><p><strong>Conclusions: </strong>These findings suggest that TRIM35 and the ^K120Ub-histone 2B epigenetic modification are molecular features of cardiomyocytes that can collectively predict dilated cardiomyopathy pathogenesis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"301-313"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300157","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":"Neutrophil Cathepsin G and Thrombosis in COVID-19.","authors":"Francesco Violi, Simona Bartimoccia, Roberto Cangemi, Cristina Nocella, Alessandra D'Amico, Alessandra Oliva, Mario Venditti, Francesco Pugliese, Claudio Maria Mastroianni, Lorenzo Ridola, Miriam Lichtner, Vincenzo Cardinale, Domenico Alvaro, Vittoria Cammisotto, Valentina Castellani, Pasquale Pignatelli, Roberto Carnevale","doi":"10.1161/CIRCRESAHA.124.324649","DOIUrl":"10.1161/CIRCRESAHA.124.324649","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"350-352"},"PeriodicalIF":16.5,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175126","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}