Circulation research最新文献

{"title":"TRIM16 Mediates K63-Linked Ubiquitination of DAB2 to Facilitate Vascular Calcification.","authors":"Zirong Lan, Qingchun Liang, Li Li, Fang Liu, An Chen, Yuanzhi Ye, Liyun Feng, Zixi Zhang, Xiuli Zhang, Jing-Song Ou, Lihe Lu, Jianyun Yan","doi":"10.1161/CIRCRESAHA.125.326520","DOIUrl":"10.1161/CIRCRESAHA.125.326520","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is highly prevalent in patients with chronic kidney disease (CKD), and the underlying mechanisms remain elusive. Several studies have indicated an important role of protein ubiquitination in vascular calcification. However, the role of E3 ubiquitin ligases in vascular calcification remains poorly understood.</p><p><strong>Methods: </strong>Calcification of vascular smooth muscle cells (VSMCs) was induced by high phosphate. CKD mouse model was induced by an adenine diet, and CKD rat model was established using 5/6 nephrectomy method. Adenovirus, siRNA (small interfering RNA), adeno-associated virus, and smooth muscle cell-specific <i>TRIM16</i> (tripartite motif 16) knockout mice were used to investigate the role of TRIM16 in vascular calcification. Immunoprecipitation-mass spectrometry, and ubiquitination assay were used to dissect how TRIM16 regulates vascular calcification.</p><p><strong>Results: </strong>Bioinformatic analysis suggested that E3 ubiquitin ligase TRIM16 could be a key modulator of vascular calcification. TRIM16 expression was increased during vascular calcification. Overexpression of <i>TRIM16</i> exacerbated VSMC calcification and aortic calcification of CKD rats. By contrast, the knockdown of <i>TRIM16</i> alleviated VSMC calcification and aortic calcification in CKD rats. Moreover, the deletion of <i>TRIM16</i> inhibited VSMC calcification and aortic calcification in VitD3 (vitamin D3)-overloaded mice and CKD mice. Mechanistically, immunoprecipitation-mass spectrometry revealed that DAB2 (disabled homolog 2) was the potential downstream target of TRIM16. Coimmunoprecipitation showed that the SPRY (SPla and the RYanodine receptor) domain of TRIM16 interacted with the proline-rich domain of DAB2. Moreover, ubiquitination assay revealed that the SPRY domain of TRIM16 is required for TRIM16-mediated K63-linked ubiquitination of DAB2 at K656 residue. Of note, the knockdown of <i>DAB2</i> inhibited TRIM16-induced VSMC calcification. Furthermore, knockdown of <i>DAB2</i> antagonized endocytosis of integrin β1 and subsequent activation of FAK (focal adhesion kinase)-STAT3 (signal transduction and transcriptional activation factor 3) signaling induced by overexpression of <i>TRIM16</i>.</p><p><strong>Conclusions: </strong>Our study for the first time demonstrates that E3 ubiquitin ligase TRIM16 catalyzes K63-ubiquitination of the endocytic adaptor DAB2, leading to endocytosis of integrin β1 and activation of FAK-STAT3 signaling, and subsequently exacerbates vascular calcification, suggesting that TRIM16-DAB2 axis is a promising therapeutic target for vascular calcification.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"551-568"},"PeriodicalIF":16.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504989","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":"Novel Mouse Model of Coronary Atherosclerosis With Myocardial Infarction: Insights Into Human CAD.","authors":"Hong Chen, Qing Wan, Jianfeng Yang, Haojie Rao, Chuansheng Xu, Pengfei Xu, Xuejian Yang, Hongyue Wang, Wei Feng, Liqing Wang, Magnus Bäck, Robert E Widdop, Feng Liu, Hong S Lu, Alan Daugherty, Shengshou Hu, Garret A FitzGerald, De-Pei Liu, Yu Huang, Weijun Jin, Miao Wang","doi":"10.1161/CIRCRESAHA.125.326409","DOIUrl":"10.1161/CIRCRESAHA.125.326409","url":null,"abstract":"<p><strong>Background: </strong>Coronary artery disease is a chronic and multifactorial disease with acute manifestations. Little is known about the concomitant impact of hypercholesterolemia and hypertension on the development of coronary atherosclerosis.</p><p><strong>Methods: </strong><i>ApoE</i> (apolipoprotein E) and <i>Scarb1</i> (scavenger receptor class B, type I), both associated with human hypercholesterolemia, were inactivated in mice by inserting a <i>Scarb1</i> knockdown cassette downstream of the <i>ApoE</i> promoter. Meanwhile, a doxycycline-inducible Ang II (angiotensin II) expression cassette was introduced. The resultant mutant mice (<i>ApoE</i>^<i>SA/SA</i>), isolated arteries, and pharmacological/genetic interventions were employed to assess the impacts of hypercholesterolemia and hypertension on coronary atherosclerosis and mechanisms.</p><p><strong>Results: </strong><i>ApoE</i>^<i>SA/SA</i> mice developed mild coronary atherosclerosis with heart failure after chronic feeding with western diet. Strikingly, additional Ang II-induced hypertension, but not norepinephrine-induced hypertension, drastically accelerated coronary atherogenesis, exhibiting endothelial erosion, myeloid cell infiltration, spontaneous plaque rupture, and myocardial infarction, which was Ang II type 1 receptor-dependent. In contrast to this severe coronary atherosclerosis, femoral arteries were resistant to atherogenesis. Proteomic profiling revealed substantial differences in vasomotor reactivity and inflammation. Endothelium-dependent dilatation of coronary arteries was highly susceptible to the combination of hypercholesterolemia and hypertension compared with femoral arteries, and a similar vulnerability was also observed in human coronary arteries. Ex vivo exposure to Ang II markedly impaired endothelium-dependent dilatation in coronary arteries, but not in femoral arteries. Consistent with its less coronary atherogenic activity, norepinephrine dilated coronary arteries while constricting femoral arteries. Furthermore, dilatation of the coronary artery was more dependent on prostaglandins than that in femoral artery. Coronary prostaglandin biosynthesis was suppressed during atherogenesis and, conversely, an elevated coronary production of prostaglandins after methotrexate administration was associated with improved endothelial function and better cardiovascular survival.</p><p><strong>Conclusions: </strong>The combination of hypercholesterolemia and Ang II-induced hypertension exerts strong synergistic effects on coronary atherogenesis. This is attributable to a selective vulnerability of coronary endothelium-dependent vasodilator responses to Ang II exposure and prostaglandin inhibition. <i>ApoE</i>^<i>SA/SA</i> represents a novel and convenient mouse model of coronary atherosclerosis with spontaneous myocardial infarction.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e106-e123"},"PeriodicalIF":16.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246725","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":"Paracrine Smooth Muscle-to-Endothelial Signaling via TNF Elevates Blood Pressure in Obesity.","authors":"Maniselvan Kuppusamy,Matteo Ottolini,Yen-Lin Chen,Zdravka Daneva,Jie Li,Caroline Heng-Mae Cheung,Natalia Rios,Rafael Radi,Gracie Garcia,Divine Nwafor,Min S Park,Alexei V Tumanov,Swapnil K Sonkusare","doi":"10.1161/circresaha.124.326069","DOIUrl":"https://doi.org/10.1161/circresaha.124.326069","url":null,"abstract":"BACKGROUNDLoss of endothelial function is a key contributor to obesity-induced hypertension. Obesity can cause chronic, low-grade inflammation, leading to abnormal blood vessel function. The release of inflammatory cytokines is commonly attributed to immune cells, but recent studies suggest that vascular cells can also release these cytokines. We tested the hypothesis that vascular wall-derived inflammatory cytokines act locally to impair endothelial function and elevate blood pressure in obesity.METHODSThe levels of inflammatory cytokines were analyzed in endothelial cells (ECs) and smooth muscle cells (SMCs) from small arteries of high-fat diet-fed mice and individuals with obesity. We utilized inducible, EC- or SMC-specific deletion and receptor inhibition studies to determine whether inflammatory signaling between SMCs and ECs can be targeted to improve endothelial function and lower blood pressure in obesity.RESULTSTNF (tumor necrosis factor) was selectively upregulated in SMCs from small arteries of obese mice and human subjects with obesity. TNF colocalized with TNFRI (TNF receptor I) at endothelial projections to SMCs or myoendothelial projections in obesity. SMC-specific deletion of TNF or EC-specific deletion of TNFRI improved endothelial function and lowered blood pressure in obese mice. Notably, deleting TNF from ECs or TNFRI from SMCs had no impact on endothelial function or blood pressure in obesity. Furthermore, the deletion of TNF from SMCs or TNFRI from ECs decreased the levels of inducible NO synthase and peroxynitrite, leading to enhanced activity of TRPV4 (transient receptor potential vanilloid 4) ion channels and improved endothelial function. In addition, specific inhibition of TNFRI also rescued endothelial function and lowered blood pressure in obesity.CONCLUSIONSOverall, these findings show that paracrine signaling from SMCs to ECs via TNF elevates blood pressure in obesity. Consequently, targeting smooth muscle TNF or endothelial TNFRI offers a potential approach for lowering blood pressure in obesity.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756060","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":"Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.","authors":"Tie-Ning Zhang, Xin-Mei Huang, Linus Li, Yue Li, Yong-Ping Liu, Xiao-Lu Shi, Qi-Jun Wu, Ri Wen, Yu-Hang Yang, Tao Zhang, Ting-Ting Gong, Fang-Hua Liu, Chun-Feng Liu, Wanshan Ning, Ni Yang","doi":"10.1161/CIRCRESAHA.124.325708","DOIUrl":"10.1161/CIRCRESAHA.124.325708","url":null,"abstract":"<p><strong>Background: </strong>Serum lactate levels are used to evaluate tissue hypoxia and predict outcomes in cases of sepsis and septic shock. Lactate can participate in a posttranslational modification known as lactylation. Myocardial depression during sepsis and septic shock is common. Here, we investigated the role of lactate in sepsis-induced myocardial depression.</p><p><strong>Methods: </strong>Septic myocardial depression in rats was induced by lipopolysaccharide administration or cecal ligation and puncture. Lactylation and protein profiles of heart tissues from the control and lipopolysaccharide groups were analyzed using proteomic analysis. Lactylation of the HADHA (trifunctional enzyme subunit alpha) at K166 and K728 was detected in septic heart tissues and lipopolysaccharide-induced cultured cells. Mutation of K166 and K728 HADHA were used to clarify the effects of HADHA lactylation on mitochondrial function, ATP production, energy metabolism, and heart function. Transcriptomic and metabolomic analyses were used to identify differentially expressed genes and differential metabolites in H9c2 (rat cardiomyoblast cell line) cells.</p><p><strong>Results: </strong>We identified 1127 lysine lactylation sites, with 83 differentially lactylated lysine sites. By integrating multifeature hybrid learning and protein language models, we identified lactylation at K166 and K728 of the HADHA as functionally important. We confirmed that lactylation at these sites was influenced by lactate levels and inhibited the HADHA activity, which disturbed mitochondrial function, ATP production, and energy metabolism. This reduction in the contraction force of cardiomyocytes can influence heart function in vitro and in vivo. Furthermore, this study revealed that sirtuin 1 and sirtuin 3 regulated the lactylation of HADHA at K166 and K728.</p><p><strong>Conclusions: </strong>This study reveals the significant impact of lactylation on cardiomyocyte metabolism. Lactate-induced HADHA lactylation disturbs cardiomyocyte mitochondrial function and metabolism and promotes sepsis-induced cardiac dysfunction. These findings inform the development of new therapeutic targets for sepsis-induced myocardial depression.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e65-e87"},"PeriodicalIF":16.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504990","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":"Integrin'g Endocytosis and Vascular Calcification in Chronic Kidney Disease.","authors":"Rolando A Cuevas,Cynthia St Hilaire","doi":"10.1161/circresaha.125.326945","DOIUrl":"https://doi.org/10.1161/circresaha.125.326945","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"27 1","pages":"569-571"},"PeriodicalIF":20.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756058","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 Platelet MCU: A Promising Therapeutic Strategy?","authors":"Kanika Jain,John Hwa","doi":"10.1161/circresaha.125.326943","DOIUrl":"https://doi.org/10.1161/circresaha.125.326943","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"10 1","pages":"493-495"},"PeriodicalIF":20.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756050","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":"Salvaged Signals, Scarred Filters: Podocyte NPRC in Diabetic Kidney Disease.","authors":"Jocelyn Cervantes,Jenny E Kanter","doi":"10.1161/circresaha.125.326944","DOIUrl":"https://doi.org/10.1161/circresaha.125.326944","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"1 1","pages":"548-550"},"PeriodicalIF":20.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756059","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":"Lactylation: A New Metabolic Signature of Sepsis-Related Cardiac Dysfunction.","authors":"Nahum F Arefeayne,Jennifer Q Kwong","doi":"10.1161/circresaha.125.326834","DOIUrl":"https://doi.org/10.1161/circresaha.125.326834","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"9 1","pages":"516-518"},"PeriodicalIF":20.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756066","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":"Dot1L-H3K79me2-Tbx6 Axis: A Novel Therapeutic Target for Preventing Cardiac Failure.","authors":"Tomás M Peralta,Laura C Zelarayán","doi":"10.1161/circresaha.125.326946","DOIUrl":"https://doi.org/10.1161/circresaha.125.326946","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"4 1","pages":"513-515"},"PeriodicalIF":20.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756063","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":"Immunoregulatory Endothelial Cells Interact With T Cells After Myocardial Infarction.","authors":"Lukas S Tombor,Till Lautenschläger,Simone F Glaser,Ariane Fischer,Maximilian Merten,Susanne Hille,Oliver Müller,Christian Kupatt,Tarik Bozoglu,Christoph Kugler,Haider Sami,Manfred Ogris,Kathrin A Stilz,Josefine Panthel,Marion Muhly-Reinholz,Lisa-Maria Kettenhausen,Lukas Zanders,Leonie Stein,Paul Kiessling,Florian Sicklinger,Florian Leuschner,Bianca Schuhmacher,Mauro Siragusa,David Rodriguez Morales,David John,Haris Kujundzic,Minh-Thuy Katschke,Emmanouil G Solomonidis,Guillermo Luxán,Stephanie Hehlgans,Franz Rödel,Christoph Kuppe,Wesley T Abplanalp,Sebastian Cremer,Stefanie Dimmeler","doi":"10.1161/circresaha.125.326145","DOIUrl":"https://doi.org/10.1161/circresaha.125.326145","url":null,"abstract":"BACKGROUNDEndothelial cells (ECs) play pivotal roles in maintaining cardiac blood supply and regulating inflammation by acting as gatekeepers for immune cell activity. This study unveils a novel immunomodulatory function of cardiac ECs following myocardial infarction.METHODSWe used single-cell RNA sequencing and spatial transcriptomics to identify EC states after acute myocardial infarction in mice. Subsequently, we mimicked the cytokine environment that was predicted to induce EC activation in cell culture studies and confirmed the results in an endothelial-specific deletion mouse model.RESULTSSingle-cell RNA sequencing analysis identified a transient myeloid CD45+CD11b+Cdh5+ immunomodulatory EC phenotype (IMEC) emerging between days 1 and 3 after myocardial infarction. IMECs derived from Cdh5+ tissue resident cells as shown by bone marrow transplantation and lineage tracing experiment. Ligand-receptor interaction predictions indicated a cytokine-mediated activation of IMECs, which we validated through in vitro experiments in cultured ECs. Notably, while cytokine treatment with IL-1β (interleukin 1β) and TGF-β (transforming growth factor β) induced mesenchymal gene expression, the addition of IFN-γ (interferon γ) facilitated the transition into the immunomodulatory phenotype. IMECs exhibited an upregulation of MHC-II (major histocompatibility complex class II) genes, along with the expression of RUNX1 and proinflammatory cytokines, such as IL-6 and IL-12. IMECs induced T-cell activation through paracrine signaling and were colocalized with T cells in vivo. Inhibition of endothelial-specific IFN-γ-signaling in mice by IFN-γ receptor 1 deletion improved the recovery after myocardial infarction.CONCLUSIONSThese findings provide insight into the role of ECs regulating adaptive immune responses following myocardial infarction, offering potential insights into therapeutic interventions for postinfarction immunomodulation.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"68 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737235","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}