Circulation researchPub Date : 2024-11-08Epub Date: 2024-10-01DOI: 10.1161/CIRCRESAHA.124.324938
Pegah Ramezani Rad, Vanasa Nageswaran, Lisa Peters, Leander Reinshagen, Johann Roessler, Szandor Simmons, Erik Asmus, Corey Wittig, Markus C Brack, Geraldine Nouailles, Emiel P C van der Vorst, Sanne L Maas, Kristina Sonnenschein, Barbara J H Verhaar, Robert Szulcek, Martin Witzenrath, Ulf Landmesser, Wolfgang M Kuebler, Arash Haghikia
{"title":"Pneumonia Induced Rise in Glucagon Promotes Endothelial Damage and Thrombogenicity.","authors":"Pegah Ramezani Rad, Vanasa Nageswaran, Lisa Peters, Leander Reinshagen, Johann Roessler, Szandor Simmons, Erik Asmus, Corey Wittig, Markus C Brack, Geraldine Nouailles, Emiel P C van der Vorst, Sanne L Maas, Kristina Sonnenschein, Barbara J H Verhaar, Robert Szulcek, Martin Witzenrath, Ulf Landmesser, Wolfgang M Kuebler, Arash Haghikia","doi":"10.1161/CIRCRESAHA.124.324938","DOIUrl":"10.1161/CIRCRESAHA.124.324938","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1116-1118"},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342678","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":"<i>LRP1</i> Repression by SNAIL Results in ECM Remodeling in Genetic Risk for Vascular Diseases.","authors":"Lu Liu, Joséphine Henry, Yingwei Liu, Charlène Jouve, Jean-Sébastien Hulot, Adrien Georges, Nabila Bouatia-Naji","doi":"10.1161/CIRCRESAHA.124.325269","DOIUrl":"10.1161/CIRCRESAHA.124.325269","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies implicate common genetic variations in the <i>LRP1</i> (low-density lipoprotein receptor-related protein 1 gene) locus at risk for multiple vascular diseases and traits. However, the underlying biological mechanisms are unknown.</p><p><strong>Methods: </strong>Fine mapping analyses included Bayesian colocalization to identify the most likely causal variant. Human induced pluripotent stem cells were genome-edited using CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9) to delete or modify candidate enhancer regions and generate <i>LRP1</i> knockout cell lines. Cells were differentiated into smooth muscle cells through a mesodermal lineage. Transcription regulation was assessed using luciferase reporter assay, transcription factor knockdown, and chromatin immunoprecipitation. Phenotype changes in cells were conducted using cellular assays, bulk RNA sequencing, and mass spectrometry.</p><p><strong>Results: </strong>Multitrait colocalization analyses pointed at rs11172113 as the most likely causal variant in <i>LRP1</i> for fibromuscular dysplasia, migraine, pulse pressure, and spontaneous coronary artery dissection. We found the rs11172113-T allele to associate with higher <i>LRP1</i> expression. Genomic deletion in induced pluripotent stem cell-derived smooth muscle cells supported rs11172113 to locate in an enhancer region regulating <i>LRP1</i> expression. We found transcription factors MECP2 (methyl CpG binding protein 2) and SNAIL (Zinc Finger Protein SNAI1) to repress <i>LRP1</i> expression through an allele-specific mechanism, involving SNAIL interaction with disease risk allele. <i>LRP1</i> knockout decreased induced pluripotent stem cell-derived smooth muscle cell proliferation and migration. Differentially expressed genes were enriched for collagen-containing extracellular matrix and connective tissue development. <i>LRP1</i> knockout and deletion of rs11172113 enhancer showed potentiated canonical TGF-β (transforming growth factor beta) signaling through enhanced phosphorylation of SMAD2/3 (Mothers against decapentaplegic homolog 2/3). Analyses of the protein content of decellularized extracts indicated partial extracellular matrix remodeling involving enhanced secretion of CYR61 (cystein rich angiogenic protein 61), a known LRP1 ligand involved in vascular integrity and TIMP3 (Metalloproteinase inhibitor 3), implicated in extracellular matrix maintenance and also known to interact with LRP1.</p><p><strong>Conclusions: </strong>Our findings support allele-specific <i>LRP1</i> expression repression by the endothelial-to-mesenchymal transition regulator SNAIL. We propose decreased <i>LRP1</i> expression in smooth muscle cells to remodel the extracellular matrix enhanced by TGF-β as a potential mechanism of this pleiotropic locus for vascular diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1084-1097"},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361212","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}
Circulation researchPub Date : 2024-11-08Epub Date: 2024-11-07DOI: 10.1161/RES.0000000000000700
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000700","DOIUrl":"https://doi.org/10.1161/RES.0000000000000700","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 11","pages":"1030-1032"},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603174","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}
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 Junming Zhu, Luyang Sun, Yi Fu, Wei Kong
{"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 Junming Zhu, Luyang Sun, Yi Fu, Wei Kong","doi":"10.1161/CIRCRESAHA.124.325152","DOIUrl":"https://doi.org/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 CaPO<sub>4</sub>-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 CaPO<sub>4</sub>-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":""},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","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}
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
{"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":"https://doi.org/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><sup><i>iΔEC</i></sup>) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (2±4 dynes/cm<sup>2</sup>) or oscillatory shear (0.5±4 dynes/cm<sup>2</sup>) 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><sup><i>iΔEC</i></sup> mice showed heightened vascular permeability. <i>Kindlin-2</i><sup><i>iΔEC</i></sup> were bred onto <i>ApoE</i><sup><i>-/-</i></sup> mice to generate <i>Kindlin-2</i><sup><i>iΔEC</i></sup>; <i>ApoE</i><sup><i>-</i></sup><sup><i>/-</i></sup> 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><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02783300.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2024-11-04","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":"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":"https://doi.org/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":""},"PeriodicalIF":16.5,"publicationDate":"2024-10-28","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}
Circulation researchPub Date : 2024-10-25Epub Date: 2024-10-01DOI: 10.1161/CIRCRESAHA.124.325305
Manako Yamaguchi, Lucas Ferreira de Almeida, Hiroki Yamaguchi, Xiuyin Liang, Jason P Smith, Silvia Medrano, Maria Luisa S Sequeira-Lopez, R Ariel Gomez
{"title":"Transformation of the Kidney into a Pathological Neuro-Immune-Endocrine Organ.","authors":"Manako Yamaguchi, Lucas Ferreira de Almeida, Hiroki Yamaguchi, Xiuyin Liang, Jason P Smith, Silvia Medrano, Maria Luisa S Sequeira-Lopez, R Ariel Gomez","doi":"10.1161/CIRCRESAHA.124.325305","DOIUrl":"10.1161/CIRCRESAHA.124.325305","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1025-1027"},"PeriodicalIF":16.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342679","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}
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
{"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":"https://doi.org/10.1161/CIRCRESAHA.124.325183","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}