Circulation research最新文献

{"title":"Salt and CHIP: <i>Tet2</i>-CH Aggravates Salt-Sensitive Hypertension in Mice.","authors":"Caitlyn Vlasschaert, Steven D Crowley, Alexander G Bick","doi":"10.1161/CIRCRESAHA.124.325364","DOIUrl":"10.1161/CIRCRESAHA.124.325364","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 9","pages":"951-953"},"PeriodicalIF":16.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399566","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":"Chronic Activation of Tubulin Tyrosination Improves Heart Function.","authors":"Niels Pietsch, Christina Y Chen, Svenja Kupsch, Lucas Bacmeister, Birgit Geertz, Marisol Herrera-Rivero, Bente Siebels, Hannah Voß, Elisabeth Krämer, Ingke Braren, Dirk Westermann, Hartmut Schlüter, Giulia Mearini, Saskia Schlossarek, Jolanda van der Velden, Matthew A Caporizzo, Diana Lindner, Benjamin L Prosser, Lucie Carrier","doi":"10.1161/CIRCRESAHA.124.324387","DOIUrl":"10.1161/CIRCRESAHA.124.324387","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (<i>Mybpc3</i> knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs).</p><p><strong>Methods: </strong>Adeno-associated virus serotype 9-mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell-derived cardiomyocytes.</p><p><strong>Results: </strong>We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell-derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs.</p><p><strong>Conclusions: </strong>This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"910-932"},"PeriodicalIF":16.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281154","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":"Arg92Leu-cTnT Alters the cTnC-cTnI Interface Disrupting PKA-Mediated Relaxation.","authors":"Melissa L Lynn,Jesus Jimenez,Romi L Castillo,Catherine Vasquez,Matthew M Klass,Anthony Baldo,Andrew Kim,Cyonna Gibson,Anne M Murphy,Jil C Tardiff","doi":"10.1161/circresaha.124.325223","DOIUrl":"https://doi.org/10.1161/circresaha.124.325223","url":null,"abstract":"BACKGROUNDImpaired left ventricular relaxation, high filling pressures, and dysregulation of Ca2+ homeostasis are common findings contributing to diastolic dysfunction in hypertrophic cardiomyopathy (HCM). Studies have shown that impaired relaxation is an early observation in the sarcomere-gene-positive preclinical HCM cohort, which suggests the potential involvement of myofilament regulators in relaxation. A molecular-level understanding of mechanism(s) at the level of the myofilament is lacking. We hypothesized that mutation-specific, allosterically mediated, changes to the cTnC (cardiac troponin C)-cTnI (cardiac troponin I) interface can account for the development of early-onset diastolic dysfunction via decreased PKA accessibility to cTnI.METHODSHCM mutations R92L-cTnT (cardiac troponin T; Arg92Leu) and Δ160E-cTnT (Glu160 deletion) were studied in vivo, in vitro, and in silico via 2-dimensional echocardiography, Western blotting, ex vivo hemodynamics, stopped-flow kinetics, time-resolved fluorescence resonance energy transfer, and molecular dynamics simulations.RESULTSThe HCM-causative mutations R92L-cTnT and Δ160E-cTnT result in different time-of-onset diastolic dysfunction. R92L-cTnT demonstrated early-onset diastolic dysfunction accompanied by a localized decrease in phosphorylation of cTnI. Constitutive phosphorylation of cTnI (cTnI-D23D24) was sufficient to recover diastolic function to non-Tg levels only for R92L-cTnT. Mutation-specific changes in Ca2+ dissociation rates associated with R92L-cTnT reconstituted with cTnI-D23D24 led us to investigate potential involvement of structural changes in the cTnC-cTnI interface as an explanation for these observations. We probed the interface via time-resolved fluorescence resonance energy transfer revealing a repositioning of the N-terminus of cTnI, closer to cTnC, and concomitant decreases in distance distributions at sites flanking the PKA consensus sequence. Implementing time-resolved fluorescence resonance energy transfer distances as constraints into our atomistic model identified additional electrostatic interactions at the consensus sequence.CONCLUSIONSThese data show that the early diastolic dysfunction observed in a subset of HCM is attributable to allosterically mediated structural changes at the cTnC-cTnI interface that impair accessibility of PKA, thereby blunting β-adrenergic responsiveness and identifying a potential molecular target for therapeutic intervention.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"249 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328759","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":"Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.","authors":"Jie Ju, Kai Wang, Fang Liu, Cui-Yun Liu, Yun-Hong Wang, Shao-Cong Wang, Lu-Yu Zhou, Xin-Min Li, Yu-Qin Wang, Xin-Zhe Chen, Rui-Feng Li, Shi-Jun Xu, Chen Chen, Mei-Hua Zhang, Su-Min Yang, Jin-Wei Tian, Kun Wang","doi":"10.1161/CIRCRESAHA.124.324733","DOIUrl":"10.1161/CIRCRESAHA.124.324733","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8 [neural precursor cell expressed developmentally downregulated protein 8]-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. Tandem mass tag (TMT)-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 (lysine residue at site 238) crotonylation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardi","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"806-821"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124985","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":"Systems Biology Approach Uncovers Candidates for Liver-Heart Interorgan Crosstalk in HFpEF.","authors":"Stefano Strocchi, Luo Liu, Rongling Wang, Steffen P Häseli, Federico Capone, David Bode, Natasha Nambiar, Tolga Eroglu, Leandro Santiago Padilla, Catherine Farrelly, Antonio Vacca, Marianna Mascagni, Christian U Oeing, Ulrich Kintscher, Simone Jung, Saskia A Diezel, Sarah V Liévano Contreras, Mingqi Zhou, Marcus Seldin, Gabriele G Schiattarella","doi":"10.1161/CIRCRESAHA.124.324829","DOIUrl":"10.1161/CIRCRESAHA.124.324829","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"873-876"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104845","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":"Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.","authors":"Akira Yoshii,Timothy S McMillen,Yajun Wang,Bo Zhou,Hongye Chen,Durba Banerjee,Melisa Herrero,Pei Wang,Naoto Muraoka,Wang Wang,Charles E Murry,Rong Tian","doi":"10.1161/circresaha.123.324103","DOIUrl":"https://doi.org/10.1161/circresaha.123.324103","url":null,"abstract":"BACKGROUNDMetabolic remodeling and mitochondrial dysfunction are hallmarks of heart failure with reduced ejection fraction. However, their role in the pathogenesis of HF with preserved ejection fraction (HFpEF) is poorly understood.METHODSIn a mouse model of HFpEF, induced by high-fat diet and Nω-nitrol-arginine methyl ester, cardiac energetics was measured by 31P NMR spectroscopy and substrate oxidation profile was assessed by 13C-isotopmer analysis. Mitochondrial functions were assessed in the heart tissue and human induced pluripotent stem cell-derived cardiomyocytes.RESULTSHFpEF hearts presented a lower phosphocreatine content and a reduced phosphocreatine/ATP ratio, similar to that in heart failure with reduced ejection fraction. Decreased respiratory function and increased reactive oxygen species production were observed in mitochondria isolated from HFpEF hearts suggesting mitochondrial dysfunction. Cardiac substrate oxidation profile showed a high dependency on fatty acid oxidation in HFpEF hearts, which is the opposite of heart failure with reduced ejection fraction but similar to that in high-fat diet hearts. However, phosphocreatine/ATP ratio and mitochondrial function were sustained in the high-fat diet hearts. We found that mitophagy was activated in the high-fat diet heart but not in HFpEF hearts despite similar extent of obesity suggesting that mitochondrial quality control response was impaired in HFpEF hearts. Using a human induced pluripotent stem cell-derived cardiomyocyte mitophagy reporter, we found that fatty acid loading stimulated mitophagy, which was obliterated by inhibiting fatty acid oxidation. Enhancing fatty acid oxidation by deleting ACC2 (acetyl-CoA carboxylase 2) in the heart stimulated mitophagy and improved HFpEF phenotypes.CONCLUSIONSMaladaptation to metabolic stress in HFpEF hearts impairs mitochondrial quality control and contributed to the pathogenesis, which can be improved by stimulating fatty acid oxidation.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328681","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000694","DOIUrl":"https://doi.org/10.1161/RES.0000000000000694","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 8","pages":"804-805"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342680","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":"Monocytes Reprogrammed by 4-PBA Potently Contribute to the Resolution of Inflammation and Atherosclerosis.","authors":"Shuo Geng, Ran Lu, Yao Zhang, Yajun Wu, Ling Xie, Blake A Caldwell, Kisha Pradhan, Ziyue Yi, Jacqueline Hou, Feng Xu, Xian Chen, Liwu Li","doi":"10.1161/CIRCRESAHA.124.325023","DOIUrl":"10.1161/CIRCRESAHA.124.325023","url":null,"abstract":"<p><strong>Background: </strong>Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis.</p><p><strong>Methods: </strong>Systems analyses integrating single-cell RNA sequencing and complementary immunologic approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming were assessed by integrated biochemical and genetic approaches. The intercellular propagation of homeostasis resolution was evaluated by coculture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high-fat diet-fed <i>ApoE</i>^<i>-/-</i> mouse model with IP 4-PBA administration. Furthermore, the selective efficacy of 4-PBA-trained monocytes was examined by IV transfusion of ex vivo trained monocytes by 4-PBA into recipient high-fat diet-fed <i>ApoE</i>^<i>-/-</i> mice.</p><p><strong>Results: </strong>In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 (intercellular adhesion molecule 1) via reducing peroxisome stress and attenuating SYK (spleen tyrosine kinase)-mTOR (mammalian target of rapamycin) signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ (peroxisome proliferator-activated receptor γ) neddylation mediated by TOLLIP (toll-interacting protein). 4-PBA-trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA-trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo.</p><p><strong>Conclusions: </strong>Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"856-872"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119127","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":"Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.","authors":"Venkata Garlapati, Qi Luo, Jens Posma, Melania Aluia, Than Son Nguyen, Kristin Grunz, Michael Molitor, Stefanie Finger, Gregory Harms, Tobias Bopp, Wolfram Ruf, Philip Wenzel","doi":"10.1161/CIRCRESAHA.123.324114","DOIUrl":"10.1161/CIRCRESAHA.123.324114","url":null,"abstract":"<p><strong>Background: </strong>Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood.</p><p><strong>Methods: </strong>Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention.</p><p><strong>Results: </strong>Cleavage-insensitive PAR2^R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7^fl/fl CX3CR1 (CX3C motif chemokine receptor 1)^Cre mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)⁺ cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF⁺/TREM (triggered receptor expressed on myeloid cells) 1⁺ macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)⁺ macrophages and, conversely, to a reduction of TF⁺/TREM1⁺ macrophages, which were also reduced in PAR2^R38E mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI.</p><p><strong>Conclusions: </strong>Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"841-855"},"PeriodicalIF":16.5,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132009","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":"Visualizing Immune Checkpoint Inhibitors Derived Inflammation in Atherosclerosis.","authors":"Lanlan Lou,Lisa Detering,Hannah Luehmann,Junedh M Amrute,Deborah Sultan,Pan Ma,Alexandria Li,Divangana Lahad,Andreas Bredemeyer,Xiuli Zhang,Gyu Seong Heo,Kory Lavine,Yongjian Liu","doi":"10.1161/circresaha.124.324260","DOIUrl":"https://doi.org/10.1161/circresaha.124.324260","url":null,"abstract":"BACKGROUNDImmune checkpoint inhibitor (ICI) usage has resulted in immune-related adverse events in patients with cancer, such as accelerated atherosclerosis. Of immune cells involved in atherosclerosis, the role of CCR2+ (CC motif chemokine receptor 2-positive) proinflammatory macrophages is well documented. However, there is no noninvasive approach to determine the changes of these cells in vivo following ICI treatment and explore the underlying mechanisms of immune-related adverse events. Herein, we aim to use a CCR2 (CC motif chemokine receptor 2)-targeted radiotracer and positron emission tomography (PET) to assess the aggravated inflammatory response caused by ICI treatment in mouse atherosclerosis models and explore the mechanism of immune-related adverse events.METHODSApoe-/- mice and Ldlr-/- mice were treated with an ICI, anti-PD1 (programmed cell death protein 1) antibody, and compared with those injected with either isotype control IgG or saline. The radiotracer 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i (extracellular loop 1 inverso) was used for PET imaging of CCR2+ macrophages. Atherosclerotic arteries were collected for molecular characterization.RESULTSCCR2 PET revealed significantly higher radiotracer uptake in both Apoe-/- and Ldlr-/- mice treated with anti-PD1 compared with the control groups. The increased expression of CCR2+ cells in Apoe-/- and Ldlr-/- mice was confirmed by immunostaining and flow cytometry. Single-cell RNA sequencing revealed elevated expression of CCR2 in myeloid cells. Mechanistically, IFNγ (interferon gamma) was essential for aggravated inflammation and atherosclerotic plaque progression following anti-PD1 treatment.CONCLUSIONSAccelerated atherosclerotic plaque inflammation triggered by anti-PD1 treatment can be noninvasively detected by 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-ECL1i PET. Aggravated plaque inflammation is time- and dose-dependent and predominately mediated by IFNγ signaling. This study warrants further investigation of CCR2 PET as a noninvasive approach to visualize atherosclerotic plaque inflammation and explore the underlying mechanism following ICI treatment.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"7 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328762","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}