Circulation research最新文献

{"title":"Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia.","authors":"Maria A Pabon,Robert M Weisbrod,Claire Castro,Haobo Li,Peng Xia,Jiayi Kang,Maddalena Ardissino,Katherine E Economy,Zihui Yang,Yanxi Shi,Eunice Kim,Anna Perillo,Leanne Barrett,Jenifer M Brown,Sanjay Divakaran,Murat Cetinbas,Ruslan I Sadreyev,Antonio de Marvao,Malissa J Wood,Nandita S Scott,Emily S Lau,Jennifer E Ho,Marcelo F Di Carli,Jason D Roh,Naomi M Hamburg,Michael C Honigberg","doi":"10.1161/circresaha.124.324606","DOIUrl":"https://doi.org/10.1161/circresaha.124.324606","url":null,"abstract":"BACKGROUNDPreeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.METHODSVenous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire-based technique in the antecubital vein followed by CD144 magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches.RESULTSSeventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation (P=7.9×10-3) and 72% decrease in cell proliferation (P=2.9×10-2). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1, INHBA, and IL1B. Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression.CONCLUSIONSIn a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"41 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887708","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":"CAR-Macrophage Therapy Alleviates Myocardial Ischemia-Reperfusion Injury.","authors":"Jiawan Wang, Heng Du, Wanrun Xie, Jinmiao Bi, Hao Zhang, Xu Liu, Yuhan Wang, Shaolong Zhang, Anhua Lei, Chuting He, Hailong Yuan, Jiahe Zhang, Yujing Li, Pengfei Xu, Siqi Liu, Yanan Zhou, Jianghua Shen, Jingdong Wu, Yihong Cai, Chaofan Yang, Zeya Li, Yingxin Liang, Yang Zhao, Jin Zhang, Moshi Song","doi":"10.1161/CIRCRESAHA.124.325212","DOIUrl":"10.1161/CIRCRESAHA.124.325212","url":null,"abstract":"<p><strong>Background: </strong>Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear.</p><p><strong>Methods: </strong>The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo.</p><p><strong>Results: </strong>FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R.</p><p><strong>Conclusions: </strong>Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1161-1174"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496114","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":"Kindlin-2 Phase Separation in Response to Flow Controls Vascular Stability.","authors":"Nina Ma, Fangfang Wu, Jiayu Liu, Ziru Wu, Lu Wang, Bochuan Li, Yuming Liu, Xue Dong, Junhao Hu, Xi Fang, Heng Zhang, Ding Ai, Jing Zhou, Xiaohong Wang","doi":"10.1161/CIRCRESAHA.124.324773","DOIUrl":"10.1161/CIRCRESAHA.124.324773","url":null,"abstract":"<p><strong>Background: </strong>Atheroprotective shear stress preserves endothelial barrier function, while atheroprone shear stress enhances endothelial permeability. Yet, the underlying mechanisms through which distinct flow patterns regulate EC integrity remain to be clarified. This study aimed to investigate the involvement of Kindlin-2, a key component of focal adhesion and endothelial adherens junctions crucial for regulating endothelial cell (EC) integrity and vascular stability.</p><p><strong>Methods: </strong>Mouse models of atherosclerosis in EC-specific <i>Kindlin-2</i> knockout mice (<i>Kindlin-2</i>^<i>iΔEC</i>) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (12±4 dynes/cm²) or oscillatory shear (0.5±4 dynes/cm²) were applied to culture ECs. Live-cell imaging, fluorescence recovery after photobleaching assay, and OptoDroplet assay were used to study the liquid-liquid phase separation (LLPS) of Kindlin-2. Co-immunoprecipitation, mutagenesis, proximity ligation assay, and transendothelial electrical resistance assay were used to explore the underlying mechanism of flow-regulated Kindlin-2 function.</p><p><strong>Results: </strong>We found that Kindlin-2 localization is altered under different flow patterns. <i>Kindlin-2</i>^<i>iΔEC</i> mice showed heightened vascular permeability. <i>Kindlin-2</i>^<i>iΔEC</i> were bred onto <i>ApoE</i>^<i>-/-</i> mice to generate <i>Kindlin-2</i>^<i>iΔEC</i>; <i>ApoE</i>^<i>-</i>^<i>/-</i> mice, which displayed a significant increase in atherosclerosis lesions. In vitro data showed that in ECs, Kindlin-2 underwent LLPS, a critical process for proper focal adhesion assembly, maturation, and junction formation. Mass spectrometry analysis revealed that oscillatory shear increased arginine methylation of Kindlin-2, catalyzed by PRMT5 (protein arginine methyltransferase 5). Functionally, arginine hypermethylation inhibits Kindlin-2 LLPS, impairing focal adhesion assembly and junction maturation. Notably, we identified R290 of Kindlin-2 as a crucial residue for LLPS and a key site for arginine methylation. Finally, pharmacologically inhibiting arginine methylation reduces EC activation and plaque formation.</p><p><strong>Conclusions: </strong>Collectively, our study elucidates that mechanical force induces arginine methylation of Kindlin-2, thereby regulating vascular stability through its impact on Kindlin-2 LLPS. Targeting Kindlin-2 arginine methylation emerges as a promising hemodynamic-based strategy for treating vascular disorders and atherosclerosis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1141-1160"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567535","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.0000000000000704","DOIUrl":"https://doi.org/10.1161/RES.0000000000000704","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 12","pages":"1120-1121"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784296","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":"Cytotoxic T Cells Drive Outcome in Inflammatory Dilated Cardiomyopathy.","authors":"Maurits A Sikking, Daniel Harding, Michiel T H M Henkens, Sophie L V M Stroeks, Max F G H M Venner, Bastien Nihant, Rick E W van Leeuwen, Silvia Fanti, Xiaofei Li, Pieter van Paassen, Christian Knackstedt, Hans-Peter Brunner-la Rocca, Vanessa P M van Empel, Job A J Verdonschot, Federica M Marelli-Berg, Stephane R B Heymans","doi":"10.1161/CIRCRESAHA.124.325183","DOIUrl":"10.1161/CIRCRESAHA.124.325183","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1193-1195"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11620291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459345","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":"In This Issue.","authors":"","doi":"10.1161/RES.0000000000000703","DOIUrl":"https://doi.org/10.1161/RES.0000000000000703","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 12","pages":"1119"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784293","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":"ANK Deficiency-Mediated Cytosolic Citrate Accumulation Promotes Aortic Aneurysm.","authors":"Hao Wu, Zhiqing Li, Liu Yang, Lin He, Hao Liu, Shiyu Yang, Qinfeng Xu, Yanjie Li, Wenqiang Li, Yiran Li, Ze Gong, Yicong Shen, Xueyuan Yang, Jiaqi Huang, Fang Yu, Li Li, Junming Zhu, Luyang Sun, Yi Fu, Wei Kong","doi":"10.1161/CIRCRESAHA.124.325152","DOIUrl":"10.1161/CIRCRESAHA.124.325152","url":null,"abstract":"<p><strong>Background: </strong>Disturbed metabolism and transport of citrate play significant roles in various pathologies. However, vascular citrate regulation and its potential role in aortic aneurysm (AA) development remain poorly understood.</p><p><strong>Methods: </strong>Untargeted metabolomics by mass spectrometry was applied to identify upregulated metabolites of the tricarboxylic acid cycle in AA tissues of mice. To investigate the role of citrate and its transporter ANK (progressive ankylosis protein) in AA development, vascular smooth muscle cell (VSMC)-specific <i>Ank</i>-knockout mice were used in both Ang II (angiotensin II)- and CaPO₄-induced AA models.</p><p><strong>Results: </strong>Citrate was abnormally increased in both human and murine aneurysmal tissues, which was associated with downregulation of ANK, a citrate membrane transporter, in VSMCs. The knockout of <i>Ank</i> in VSMCs promoted AA formation in both Ang II- and CaPO₄-induced AA models, while its overexpression inhibited the development of aneurysms. Mechanistically, ANK deficiency in VSMCs caused abnormal cytosolic accumulation of citrate, which was cleaved into acetyl coenzyme A and thus intensified histone acetylation at H3K23, H3K27, and H4K5. Cleavage under target and tagmentation analysis further identified that ANK deficiency-induced histone acetylation activated the transcription of inflammatory genes in VSMCs and thus promoted a citrate-related proinflammatory VSMC phenotype during aneurysm diseases. Accordingly, suppressing citrate cleavage to acetyl coenzyme A downregulated inflammatory gene expression in VSMCs and restricted ANK deficiency-aggravated AA formation.</p><p><strong>Conclusions: </strong>Our studies define the pathogenic role of ANK deficiency-induced cytosolic citrate accumulation in AA pathogenesis and an undescribed citrate-related proinflammatory VSMC phenotype. Targeting ANK-mediated citrate transport may emerge as a novel diagnostic and therapeutic strategy in AA.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1175-1192"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603212","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.0000000000000704","DOIUrl":"https://doi.org/10.1161/RES.0000000000000704","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 12","pages":"1120-1121"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540371","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":"Correction to: Blunted Cardiac Mitophagy in Response to Metabolic Stress Contributes to HFpEF.","authors":"","doi":"10.1161/RES.0000000000000702","DOIUrl":"https://doi.org/10.1161/RES.0000000000000702","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 12","pages":"e154"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784286","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":"Salt's Sex-Specific Impact of Gut Microbiota in Hypertension.","authors":"Selam Desta, Claude F Albritton, Annet Kirabo","doi":"10.1161/CIRCRESAHA.124.325719","DOIUrl":"10.1161/CIRCRESAHA.124.325719","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 12","pages":"1138-1140"},"PeriodicalIF":16.5,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11623195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784302","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}