Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"<i>ATVB</i> Journal Awards at Vascular Discovery.","authors":"Ann Marie Schmidt","doi":"10.1161/ATVBAHA.125.322551","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322551","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 4","pages":"459-460"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727585","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":"GSDMD Deficiency Attenuates the Development of Ascending Aortic Dissections in a Novel Mouse Model.","authors":"Muhammad J Javed, Rachael M Howard, Hua Li, Laura Carrasco, Marvin L S Dirain, Gang Su, Guoshuai Cai, Gilbert R Upchurch, Zhihua Jiang","doi":"10.1161/ATVBAHA.124.321740","DOIUrl":"10.1161/ATVBAHA.124.321740","url":null,"abstract":"<p><strong>Background: </strong>Mechanisms driving the development of type A aortic dissection (TAD) are currently poorly understood, and animal models of spontaneous TAD are limited. In the present study, we developed a novel mouse TAD model and evaluated the role of GSDMD (gasdermin D) in TAD development.</p><p><strong>Methods: </strong>TADs were created by treating the ascending aorta of adult C57BL/6J mice with Act E (active elastase) and β-aminopropionitrile. The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms were explored using bulk RNA sequencing of specimens collected at multiple time points. With this novel TAD model, we conducted additional experiments to investigate the impact of GSDMD deficiency on TAD formation.</p><p><strong>Results: </strong>Ascending aortas challenged with Act E and β-aminopropionitrile developed pathology featuring the early onset of intimomedial tears (complete penetration) and intramural hematomas, followed by progressive medial loss and aortic dilation. Ingenuity pathway analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory microenvironment, rather than general inflammation, promotes the onset of TADs by specifically recruiting neutrophils to the aortic wall. At later stages, T cell-mediated immune injury emerged as the primary driver of pathology. Gsdmd deficiency attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect correlated with a reduced cell death and decreased T-cell infiltration in TADs. Notably, cleaved GSDMD was detected in human TADs but was absent in healthy aortas.</p><p><strong>Conclusions: </strong>A novel mouse TAD model was developed, specifically targeting the ascending aorta. This model generates a unique microenvironment that activates specific immune cell subsets, driving the onset and subsequent remodeling of TADs. Consistently, Gsdmd deficiency mitigates TAD development, likely by modulating cell death and T-cell responses. This model provides a valuable tool for studying immune injury mechanisms in TAD pathogenesis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"541-556"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405552","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":"Transcytosis of LDL Across Arterial Endothelium: Mechanisms and Therapeutic Targets.","authors":"Israel O Bolanle, Gaetan C de Liedekerke Beaufort, Peter D Weinberg","doi":"10.1161/ATVBAHA.124.321549","DOIUrl":"10.1161/ATVBAHA.124.321549","url":null,"abstract":"<p><p>Transport of LDL (low-density lipoprotein) from plasma to arterial intima is thought to be rate limiting in the development of atherosclerosis. Its variation likely determines where lesions develop within arteries and might account for some of the currently unexplained difference in disease susceptibility between individuals. It may also be critical in the development of lipid-rich, unstable plaques. Mechanisms have been controversial but recent evidence suggests that caveolar transcytosis across endothelial cells is the dominant pathway. Receptors involved are LDLR (LDL receptor), SR-B1 (scavenger receptor class B type 1), and ALK1 (activin receptor-like kinase 1). The role of LDLR is influenced by IL-1β (interleukin-1β); the role of SR-B1 by HDL (high-density lipoprotein), DOCK4 (dedicator of cytokinesis 4), GPER (G-protein-coupled estrogen receptor), and HMGB1 (high mobility group box 1); and the role of ALK1 by BMP (bone morphogenetic protein) 9. Additionally, BMP4 stimulates transcytosis and FSTL1 (follistatin-like 1 protein) inhibits it. Fundamental transcytotic mechanisms include caveola formation, undocking, trafficking, and docking; they are influenced by cholesterol-lowering agents, MYDGF (myeloid-derived growth factor), MFSD2a (major facilitator superfamily domain containing 2a) in the blood-brain barrier, and inhibitors of dynamin-2 and tubulin polymerization. The relative merits of different therapeutic approaches are discussed, with statins, colchicine, benzimidazoles, and metformin being existing drugs that might be repurposed and salidroside and glycyrrhizic acid being nutraceuticals worth investigating. Finally, we discuss evidence against the ferry-boat model of transcytosis, the contributions of receptor-mediated, fluid-phase, and active transcytosis, and where inhibition of transcytosis might be most beneficial.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"468-480"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514254","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":"Restoring Vascular Smooth Muscle Cell Mitochondrial Function Attenuates Abdominal Aortic Aneurysm in Mice.","authors":"Yaozhong Liu, Minzhi Yu, Huilun Wang, Kristen Hong Dorsey, Yalun Cheng, Ying Zhao, Yonghong Luo, Guizhen Zhao, Yang Zhao, Haocheng Lu, Yongjie Deng, Wenjuan Mu, Hongyu Liu, Xiaokang Wu, Zhenguo Wang, Jifeng Zhang, Lin Chang, Y Eugene Chen, Anna Schwendman, Yanhong Guo","doi":"10.1161/ATVBAHA.124.321730","DOIUrl":"10.1161/ATVBAHA.124.321730","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysm (AAA) is a complex vascular pathology without pharmaceutical interventions. This study aimed to evaluate whether restoring vascular smooth muscle cell (VSMC) mitochondrial function could prevent AAA development.</p><p><strong>Methods: </strong>Ang II (angiotensin II)-induced AAA was established in <i>Ldlr</i>-deficient mice, and the gene expression profiles in abdominal aortic tissues exhibiting varying degrees of severity were analyzed. Synthetic high-density lipoprotein (sHDL) formulated with Apoa1 mimetic peptide and phospholipids was evaluated for the protective effects on VSMC mitochondria. The therapeutic efficacy of sHDL was further investigated in Ang II-infusion and PPE (porcine pancreatic elastase)-induced AAA models.</p><p><strong>Results: </strong>VSMC mitochondrial damage intensified gradually during AAA development, which was confirmed in distinct AAA animal models and human tissues. sHDL accumulated in the aneurysmatic lesions and restored mitochondrial DNA levels and the expression of genes related to oxidative phosphorylation following Ang II infusion. In mouse primary VSMCs, sHDL maintained mitochondrial homeostasis by suppressing the upregulation of DRP1 (dynamin-related protein 1), a protein involved in mitochondrial fission, reducing the generation of reactive oxygen species, preventing the loss of mitochondrial membrane potential, and preserving mitochondrial respiratory capacity. Administration of sHDL decreased Ang II-induced AAA incidence (control versus treatment, 76% versus 40%; <i>P</i><0.05) and maximum aortic diameters. The protective effects of sHDL were further validated in the PPE model, with reductions observed in maximum aortic diameters and aortic mitochondrial DNA loss. Post-Ang II infusion, administration of sHDL improved VSMC mitochondrial function and suppressed aneurysm growth in Apoe-deficient mice. Human AAA is characterized by mitochondrial dysfunction, and liver-derived HDL (high-density lipoprotein) components play a pivotal role in regulating gene expression in aortic tissues.</p><p><strong>Conclusions: </strong>VSMC mitochondrial damage is a pivotal factor in the development of AAA. The utilization of sHDL nanoparticles represents a promising novel therapeutic approach for AAA, aimed at restoring VSMC mitochondrial function.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"523-540"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405567","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":"Age-Related Impairments in Immune Cell Efferocytosis and Autophagy Hinder Atherosclerosis Regression.","authors":"Dominique M Boucher, Sabrina Robichaud, Victoria Lorant, Jonathan S Leon, Issraa Suliman, Adil Rasheed, Leah I Susser, Christina Emerton, Michele Geoffrion, Erica De Jong, Dawn M E Bowdish, Masanori Aikawa, Elena Aikawa, Sasha A Singh, Katey J Rayner, Mireille Ouimet","doi":"10.1161/ATVBAHA.124.321662","DOIUrl":"10.1161/ATVBAHA.124.321662","url":null,"abstract":"<p><strong>Background: </strong>Aging is a well-established risk factor for the development and progression of atherosclerosis, but the molecular mechanisms underlying this relationship remain poorly defined, and its role in atherosclerosis regression is unknown. To uncover age-related alterations that may impair atherosclerosis regression, we investigated the response of young and old macrophages to atherogenic lipoproteins in vitro and in vivo.</p><p><strong>Methods: </strong>Metabolic and proteomic studies were performed in vitro using macrophages differentiated from the bone marrow of young or old mice. To test the role of immune cell aging in atherosclerosis regression, bone marrow from young and old donors was transplanted into irradiated young recipient mice expressing gain-of-function AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9). Following 14 weeks of Western diet feeding, atherosclerosis regression was induced by switching to a standard laboratory diet for 4 weeks.</p><p><strong>Results: </strong>Compared with young macrophages, old macrophages accumulated more lipid droplets upon lipid loading with the pro-atherogenic lipoprotein aggregated LDL (low-density lipoprotein), accompanied by a failure to proportionally induce autophagy and cholesterol efflux. Proteomic analysis of bone marrow-derived macrophages revealed that pathways related to endocytosis, engulfment, and phagocytosis were downregulated in old lipid-loaded macrophages. Functional studies confirmed a reduction in efferocytic capacity in old macrophages. In recipient mice transplanted with old bone marrow, atherosclerosis regression was impaired, as evidenced by inefficient resolution of circulating inflammatory cell levels, reduced activation of plaque autophagy and apoptotic cell clearance, and persistent plaque CD45⁺ and CD68⁺ content.</p><p><strong>Conclusions: </strong>Aging impairs macrophage function through reduced efferocytosis and autophagy activation, limiting atherosclerosis regression. These results highlight the need to better define the mechanisms linking aging to atherosclerosis to develop targeted therapies for the aging population.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"481-495"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405548","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":"Mechanotransduction in the Perivascular Adipose Tissue.","authors":"Stephanie W Watts, Teresa Krieger-Burke, Rance Nault, G Andres Contreras","doi":"10.1161/ATVBAHA.124.321688","DOIUrl":"10.1161/ATVBAHA.124.321688","url":null,"abstract":"<p><p>Perivascular adipose tissue is of compelling interest when considering tissue mechanotransduction. Because of its location around a vessel, perivascular adipose tissue experiences from high (artery) to low (vein) pressures, pressures that are cyclical in nature. With blood pressure change, such as the elevation of pressure in hypertension, the question has been raised as to whether perivascular adipose tissue senses such changes, evidenced by a response that can be genetic, structural, or mechanical in nature. Here, we briefly review the following knowledge and data that support the ability of perivascular adipose tissue to both (mechano)sense and (mechano)respond.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"461-467"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405553","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":"TRPV4 Promotes Vascular Calcification by Directly Associating With and Activating β-Catenin.","authors":"Menglu Yuan, Qi Li, Zhiwei Wang, Liangju Liu, Chengyuan Wen, Guizhu Liu, Fan Yu, Lei Feng, Liu Yang","doi":"10.1161/ATVBAHA.124.321793","DOIUrl":"10.1161/ATVBAHA.124.321793","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification contributes to increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. Currently, there are no effective therapeutic strategies to prevent or reverse vascular calcification. TRPV4 (transient receptor potential channel V4), a key Ca²⁺-permeable channel, plays an important role in various diseases. However, the role and mechanism of TRPV4 in vascular calcification have not yet been elucidated.</p><p><strong>Methods: </strong>The effects of TRPV4 on vascular calcification were explored in vitro and in vivo. TRPV4 interactome assessment and molecular docking were performed to investigate the mechanism and specific therapeutic strategy for vascular calcification.</p><p><strong>Results: </strong>TRPV4 was substantially upregulated in high inorganic phosphate-induced calcified vascular smooth muscle cells (SMCs) and calcified aortas from cholecalciferol (vitamin D3)-overloaded mice. TRPV4 overexpression increased the expression of the osteochondrogenic markers Runx2 (runt-related transcription factor 2), Msx2 (Msh homeobox 2), and Sox9 (SRY-box transcription factor 9) and exacerbated high inorganic phosphate-induced vascular SMC calcification in a Ca²⁺ influx-dependent manner. In contrast, TRPV4 deficiency or inactivation significantly inhibited vascular SMC calcification under high inorganic phosphate conditions. Moreover, compared with that in control littermates, SMC-specific TRPV4 deficiency in mice alleviated vitamin D3-induced and 5/6 nephrectomy-induced vascular calcification. Mechanistically, TRPV4 interacted with β-catenin and activated β-catenin/TCF (T-cell factor) transcriptional activity via Ca²⁺/ASK1 (apoptosis signal regulating kinase 1)/p38 signaling. β-Catenin knockdown abolished the effects of TRPV4 overexpression on vascular SMC calcification. TRPV4/β-catenin interaction is pivotal for maintaining TRPV4/Ca²⁺-induced ASK1/p38/β-catenin activation. Hesperidin, a natural product found in citrus fruits, effectively disrupted TRPV4/β-catenin interaction, thereby inhibiting ASK1/p38/β-catenin activity and preventing vascular calcification.</p><p><strong>Conclusions: </strong>Our study identified TRPV4 as a new pathogenic factor for vascular calcification that directly associates with and activates β-catenin. Blocking the TRPV4/β-catenin interaction through hesperidin suppressed the progression of vascular calcification and may be an effective precision strategy to address vascular calcification.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e101-e117"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456725","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: High-Density Lipoprotein Lipid and Protein Cargo and Cholesterol Efflux Capacity Before and After Bariatric Surgery.","authors":"","doi":"10.1161/ATV.0000000000000184","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000184","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 4","pages":"e163"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727590","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":"ApoM and Major Adverse Cardiovascular Events in Chronic Kidney Disease: A Prospective Cohort Study.","authors":"Julia T Stadler, Andrea Borenich, Line Stattau Bisgaard, Sasha S Bjergfelt, Sarunja Vijayakumar, Line Melholt, Insa E Emrich, Ditte Hansen, Susanne Bro, Christina Christoffersen, Gunnar H Heine, Gunther Marsche","doi":"10.1161/ATVBAHA.124.322367","DOIUrl":"10.1161/ATVBAHA.124.322367","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD). APOM plays a critical role in reverse cholesterol transport by facilitating the formation of pre-β-HDL (high-density lipoprotein) and enabling the binding of S1P (sphingosine-1-phosphate) to HDL, a complex involved in several antiatherogenic processes. In this study, we sought to investigate the potential association between plasma APOM levels and the risk of adverse cardiovascular outcomes in individuals with CKD.</p><p><strong>Methods: </strong>Plasma APOM levels were quantified using a sandwich ELISA-based assay. Plasma S1P levels were measured by high-performance liquid chromatography. The primary end point was a composite of major adverse cardiovascular events (MACE) and all-cause mortality.</p><p><strong>Results: </strong>In this secondary analysis of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation), 463 nondialysis patients with CKD stages G2 to G4 were included. Plasma APOM levels exhibited a significant inverse association with the risk of MACE (standardized hazard ratio, 0.60 [95% CI, 0.49-0.75]; <i>P</i><0.001) and all-cause mortality (standardized hazard ratio, 0.63 [95% CI, 0.48-0.83]; <i>P</i><0.001). This inverse association with MACE remained robust after adjusting for established cardiovascular and renal risk factors. These findings were further corroborated in an independent cohort of 822 patients with CKD from the Copenhagen CKD study. Plasma S1P levels showed an inverse association with MACE in univariable analyses; however, this relationship lost statistical significance after multivariable adjustments.</p><p><strong>Conclusions: </strong>Our findings demonstrate a significant association between low plasma APOM levels and an increased risk of MACE in patients with CKD. These results suggest that APOM may play a role in cardiovascular protection in this vulnerable population.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"496-505"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565823","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":"Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice.","authors":"Yang Zhou, Dong Wang, Juhong Wu, Yingying Qi, Meiru Song, Huiqiao Yao, Christopher Kai Liao, Haili Lin, Meijuan Huang, Dexiang Zhuo, Longguang Jiang, Cai Yuan, Yuanzhong Chen, Mingdong Huang, Jinyu Li, Peng Xu","doi":"10.1161/ATVBAHA.124.322145","DOIUrl":"10.1161/ATVBAHA.124.322145","url":null,"abstract":"<p><strong>Background: </strong>FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.</p><p><strong>Methods: </strong>A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI^-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.</p><p><strong>Results: </strong>Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (half maximal inhibitory concentration of 0.17 μmol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI^-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.</p><p><strong>Conclusions: </strong>This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e150-e162"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514545","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}