Circulation research最新文献

{"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":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"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>^<i>iΔEC</i>) were used to study the role of Kindlin-2 in atherogenesis. Pulsatile shear (2±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><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02783300.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"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":null,"pages":null},"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}

{"title":"Cell-Free RNA Signatures in Maternal Blood with Fetal Congenital Heart Disease.","authors":"Matthew Alonzo, Zhaohui Xu, Yang Yu, Shiqiao Ye, Cankun Wang, Jerry Wang, Megan McNutt, Jakob Bering, Qin Ma, Karen Texter, Vidu Garg, Ming-Tao Zhao","doi":"10.1161/CIRCRESAHA.124.325024","DOIUrl":"10.1161/CIRCRESAHA.124.325024","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361213","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":"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":null,"pages":null},"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}

{"title":"HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.","authors":"Xi Fang,Åsa B Gustafsson","doi":"10.1161/circresaha.124.325501","DOIUrl":"https://doi.org/10.1161/circresaha.124.325501","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":20.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490436","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 Responsive Gut Microbiota Induces Sex Specific Blood Pressure Changes.","authors":"Pritam Bardhan,Xue Mei,Ngoc Khanh Lai,Blair Mell,Ramakumar Tummala,Sachin Aryal,Ishan Manandhar,Hyeongu Hwang,Tania Akter Jhuma,Rohit R Atluri,Jun Kyoung,Ying Li,Bina Joe,Hong-Bao Li,Tao Yang","doi":"10.1161/circresaha.124.325056","DOIUrl":"https://doi.org/10.1161/circresaha.124.325056","url":null,"abstract":"BACKGROUNDTryptophan metabolism is important in blood pressure regulation. The tryptophan-indole pathway is exclusively mediated by the gut microbiota. ACE2 (angiotensin-converting enzyme 2) participates in tryptophan absorption, and a lack of ACE2 leads to changes in the gut microbiota. The gut microbiota has been recognized as a regulator of blood pressure. Furthermore, there is ample evidence for sex differences in the gut microbiota. However, it is unclear whether such sex differences impact blood pressure differentially through the tryptophan-indole pathway.METHODSTo study the sex-specific mechanisms of gut microbiota-mediated tryptophan-indole pathway in hypertension, we generated a novel rat model with Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-targeted deletion of Ace2 in the Dahl salt-sensitive rat. Cecal microbiota transfers from donors of both sexes to female S recipients were performed. Also, Dahl salt-sensitive rats of both sexes were orally gavaged with indole to investigate blood pressure response.RESULTSThe female gut microbiota and its tryptophan-indole pathway exhibited greater buffering capacity when exposed to tryptophan, due to Ace2 deficiency, and salt. In contrast, the male gut microbiota and its tryptophan-indole pathway were more vulnerable. Female rats with male cecal microbiota responded to salt with a higher blood pressure increase. Indole, a tryptophan-derived metabolite produced by gut bacteria, increased blood pressure in male but not in female rats. Moreover, salt altered host-mediated tryptophan metabolism, characterized by reduced serum serotonin of both sexes and higher levels of kynurenine derivatives in the females.CONCLUSIONSWe uncovered a novel sex-specific mechanism in the gut microbiota-mediated tryptophan-indole pathway in blood pressure regulation. Salt tipped the tryptophan metabolism between the host and gut microbiota in a sex-dependent manner. Our study provides evidence for a novel concept that gut microbiota and its metabolism play sex-specific roles in the development of salt-sensitive hypertension.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":20.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488265","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":"https://doi.org/10.1161/circresaha.124.325183","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":20.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486329","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":"https://doi.org/10.1161/CIRCRESAHA.124.325183","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"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}