Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Endothelium- and Fibroblast-Derived C-Type Natriuretic Peptide Prevents the Development and Progression of Aortic Aneurysms.","authors":"Aisah A Aubdool, Amie J Moyes, Cristina Pérez-Ternero, Reshma S Baliga, Jasspinder Sanghera, M Taaha Syed, Kareemah Jaigirdah, Anmolpreet K Panesar, Janice C Tsui, Yanming Li, Hernan G Vasquez, Ying H Shen, Scott A LeMaire, Juliette Raffort-Lareyre, Ziad Mallat, Hong S Lu, Alan Daugherty, Adrian J Hobbs","doi":"10.1161/ATVBAHA.124.322350","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322350","url":null,"abstract":"<p><strong>Background: </strong>Thoracic aortic aneurysm (AA) and abdominal AA are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Because such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.</p><p><strong>Methods: </strong>Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP^-/-), fibroblast-restricted (fbCNP^-/-), global CNP (gbCNP^-/-), or global NPR-C^-/- mice infected with an adeno-associated virus expressing a proprotein convertase subtilisin/kexin type 9 gain-of-function mutation or backcrossed to an apoE^-/- background. At 28 days, aortas were harvested for RT-qPCR and histological analyses. CNP (0.2 mg/kg per day) was infused to rescue any adverse phenotype.</p><p><strong>Results: </strong>Aneurysmal tissue from patients with thoracic AA and abdominal AA revealed that CNP and NPR-C (natriuretic peptide receptor-C) expression were overtly perturbed. ecCNP^-/-, fbCNP^-/-, and gbCNP^-/- mice exhibited an aggravated phenotype compared with wild-type mice in both ascending and suprarenal aortas, exemplified by greater dilation, fibrosis, elastin degradation, and macrophage infiltration. CNP and NPR-C expression was also dysregulated in murine thoracic AA and abdominal AA, accompanied by increased accumulation of mRNA encoding markers of inflammation, extracellular matrix remodeling/calcification, fibrosis, and apoptosis. CNP also prevented activation of isolated macrophages and vascular smooth muscle cells. An essentially identical phenotype was observed in NPR-C^-/- mice and while administration of CNP protected against disease severity in wild-type animals, this phenotypic rescue was not apparent in NPR-C^-/- mice.</p><p><strong>Conclusions: </strong>Endothelium- and fibroblast-derived CNP, via NPR-C activation, plays important roles in attenuating AA formation by preserving aortic structure and function. Therapeutic strategies aimed at mimicking CNP bioactivity hold potential to reduce the need for surgical intervention.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771220","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":"Procoagulant Effect of Neutrophil Extracellular Traps, Activated Platelets, and Endothelial Cells in Patients After TAVR.","authors":"Wei Wu, Dongxia Tong, Wei Xia, Bin Song, Guangwen Li, Lihui Zhou, Fangyu Xie, Chunquan Zhang, Yvhao Liu, Haiyang Wang, Zhaona Du, Yibing Shao, Jihe Li","doi":"10.1161/ATVBAHA.124.322376","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322376","url":null,"abstract":"<p><strong>Background: </strong>Patients with severe aortic stenosis, undergoing transcatheter aortic valve replacement (TAVR), are more likely to develop thrombotic complications. However, the definite mechanisms underlying the hypercoagulation state remain unclear to date. Our objectives were to explore whether and how neutrophil extracellular traps (NETs) play a procoagulant role in patients after TAVR alone or TAVR with percutaneous coronary intervention within 1 year and further to evaluate their interactions with platelets and endothelial cells.</p><p><strong>Methods: </strong>The levels of plasma NETs, platelets, and endothelial cell activation markers were analyzed by ELISA. NET formation was observed by immunofluorescence. Procoagulant activity was measured by clotting time, fibrin, and TAT (thrombin-antithrombin) complex generation assays. Phosphatidylserine exposure on cells was assessed by flow cytometry.</p><p><strong>Results: </strong>Compared with pre-TAVR, controls, or severe aortic stenosis without TAVR patients, the plasma NET levels in patients after TAVR alone, especially TAVR with percutaneous coronary intervention, increased from 7 days, peaking at 3 months, and then gradually decreased until the 12th month. Furthermore, neutrophils and plasma from patients post-TAVR are more prone to promote NET formation; NETs from these patients markedly decreased clotting time and increased fibrin and TAT generation. Additionally, a high concentration of NETs induced platelet aggregation and exerted a strong cytotoxic effect on endothelial cells and transformed them into a procoagulant phenotype.</p><p><strong>Conclusions: </strong>These results lead us to believe that NETs contribute to the hypercoagulability in patients post-TAVR. Our study may provide a new target for preventing thrombotic complications in patients post-TAVR by blocking NET generation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771239","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":"ALKBH5 Regulates Macrophage Senescence and Accelerates Atherosclerosis by Promoting CCL5 m⁶A Modification.","authors":"Rifeng Gao, Jiaran Shi, Yang Lyu, Bichen Ren, Wei Wei, Jiahui Cheng, Juntao Chen, Yan Zhou, Jianxin Chen, Xiaolei Sun, Jun Jiang, Bo Li, Kun Yang","doi":"10.1161/ATVBAHA.125.322508","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322508","url":null,"abstract":"<p><strong>Background: </strong>Senescent foamy macrophages are key drivers of atherosclerosis and plaque instability. N⁶-methyladenosine (m⁶A) modification of RNA plays an important role in the development of various diseases including aging. Here, we aim to investigate the role of m⁶A modification of RNA in the formation of senescent foamy macrophages in atherosclerosis.</p><p><strong>Methods: </strong>To assess m⁶A methylation, macrophages were isolated from the atherosclerotic plaques of patients with atherosclerosis, and Apoe^-/- mice were fed a high-fat diet using CD68⁺ magnetic beads. An ALKBH5 (alkB homolog 5)^f/f, Lyz2 (lysozyme 2)^Cre, Apoe^-/- mouse model was generated to determine the infiltration of senescent foamy macrophages into plaques and atherosclerosis progression. Methylated RNA immunoprecipitation, RNA immunoprecipitation sequencing, and dual-luciferase assays were performed to explore the mechanisms underlying the ALKBH5-mediated formation of senescent foamy macrophages.</p><p><strong>Results: </strong>Decreased m⁶A methylation and increased ALKBH5 expression were observed in arterial plaques and infiltrating macrophages from patients and mice with atherosclerosis. Compared with control mice, ALKBH5^f/f, Lyz2^Cre, Apoe^-/- mice exhibited fewer atherosclerosis plaques with greater stability, which was attributed to the suppression of senescent foamy macrophage formation and senescence-associated secretory phenotype. In addition, ALKBH5 deletion reduced the mRNA expression level of CCL5 (CC chemokine ligand 5) by increasing m⁶A methylation in macrophages, which disrupts the stability of CCL5 mRNA. Mechanistically, ALKBH5 promoted senescent foamy macrophage formation through the CCL5/CCR5 (CC chemokine receptor 5)/autophagy signaling pathway. CCL5 also recruited CD8⁺ IFN (interferon)γ⁺ T cells via the CCL5-CCR5 axis. The ALKBH5 inhibitor IOX1 and the CCR5 antagonist maraviroc were identified as potential clinical interventions for inhibiting senescent foamy macrophage formation and atherosclerosis progression.</p><p><strong>Conclusions: </strong>Myeloid ALKBH5 deletion attenuates atherosclerosis progression by suppressing the formation of senescent foamy macrophages and the recruitment of CD8⁺IFNγ⁺ T cells. These findings identify ALKBH5, CCL5, and CCR5 as novel therapeutic targets for atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771266","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":"Exploring the Impact of Intermittent Fasting on Vascular Function and the Immune System: A Narrative Review and Novel Perspective.","authors":"Elliot L Graham, Tiffany L Weir, Christopher L Gentile","doi":"10.1161/ATVBAHA.125.322692","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322692","url":null,"abstract":"<p><p>Vascular function is a critical determinant of cardiovascular health and all-cause mortality. Recent studies have suggested that intermittent fasting, a popular dietary strategy, elicits beneficial effects on vascular function. These studies also suggest that fasting-mediated improvements in vascular function coincide with reductions in systemic inflammation. However, the mechanisms that connect fasting, the immune system, and vascular function remain largely underexplored. The current review summarizes the effects of different intermittent fasting modalities on vascular health, focusing on endothelial dysfunction and arterial stiffness, 2 critical indices of vascular function. Improvements in vascular function are associated with reduced inflammation and are mechanistically linked to decreased circulating immune cells and their accumulation in the vascular wall and perivascular tissue. Recent data show that fasting redistributes circulating and tissue-resident immune cells to the bone marrow, affecting their inflammatory actions. However, there is no direct evidence relating immune cell redistribution to cardiovascular health. By relating fasting-induced immune cell redistribution to reduced inflammation and improved vascular function, we propose an exciting avenue of further exploration is determining whether fasting-induced immune cell redistribution impacts cardiovascular health.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771222","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":"Colchicine Inhibits Smooth Muscle Cell Phenotypic Switch and Aortic Dissection in Mice.","authors":"Hui Jiang, Yaping Zhao, Mei Jin, Zhidan Zhang, Li Wang, Xiang Cheng, Yu Huang, Zhiping Liu, Jianping Weng, Suowen Xu","doi":"10.1161/ATVBAHA.124.322252","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322252","url":null,"abstract":"<p><strong>Background: </strong>Aortic dissection (AD) is a severe cardiovascular disorder characterized by intimal tearing and subsequent delamination of the aortic wall. The pathogenesis of AD primarily involves the phenotypic switch of vascular smooth muscle cells (VSMCs), degradation of the extracellular matrix, and chronic vascular inflammation. Colchicine, an alkaloid derived from <i>Colchicum autumnale L</i>, is a Food and Drug Administration-approved anti-inflammatory drug with established therapeutic applications in cardiovascular diseases. However, its potential role in modulating the development or progression of AD remains largely unexplored.</p><p><strong>Methods: </strong>To investigate the effects of colchicine on AD, a β-aminopropionitrile-induced AD mouse model was used. Colchicine was administered via oral gavage over a 3-week period to evaluate its impact on the incidence and mortality of AD in male C57BL/6J mice. Transcriptome sequencing was performed to identify genes and signaling pathways regulated by colchicine. Additionally, in vitro experiments using primary rat VSMCs were conducted to elucidate the mechanisms underlying colchicine-mediated regulation of VSMC phenotypic switch.</p><p><strong>Results: </strong>Colchicine demonstrated a protective effect against AD by attenuating vascular inflammation and suppressing VSMC phenotypic switch. Mechanistically, colchicine reverses VSMC phenotypic switch at least partially by modulating the expression of myocardin, a key regulator of VSMC contractile phenotype. Transcriptomic analysis further revealed specific genes and pathways influenced by colchicine, providing insights into its molecular mechanisms of action.</p><p><strong>Conclusions: </strong>This study identifies colchicine as a potential therapeutic drug for AD, highlighting its ability to mitigate hallmark pathological processes such as vascular inflammation and VSMC phenotypic switch. These findings offer a foundation base for the repurposed clinical application of colchicine in AD, which warrants further clinical investigation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771268","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":"Emerging Role of Leptin in Vascular and Placental Dysfunction in Preeclampsia.","authors":"Mona Elgazzaz, Amalia Brawley, Desmond Moronge, Jessica L Faulkner","doi":"10.1161/ATVBAHA.124.321676","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321676","url":null,"abstract":"<p><p>Leptin is a well-known metabolic hormone that plays diverse roles in various body functions, including growth, reproduction, and blood pressure regulation. In pregnancy, leptin produced from the placenta is crucial for ensuring proper fetal development and angiogenesis; however, pathological increases in leptin in maternal circulation are strongly associated with vascular endothelial dysfunction and preeclampsia. Leptin has a strong role in fertility and healthy pregnancy; however, numerous clinical reports over the last 2 decades show that leptin levels pathologically increase in patients with preeclampsia independent of metabolic status (ie, obesity). Despite this strong correlation, the role of leptin in preeclampsia is largely unexplored compared with other biomarkers likely due to differences in placental leptin production among mammals. Emerging literature has recently begun to shed light on this hormone in preeclampsia pathogenesis and uncovered some key mechanisms whereby pathologically elevated leptin production leads to cardiovascular complications for pregnant women.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771275","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":"Sex-Divergent Blood Pressure Associations With Multiorgan System Metabolic Stress-Brief Report.","authors":"Alan C Kwan, Minhao Wang, Hongwei Ji, Brian Claggett, David Ouyang, Hirsh D Trivedi, Sonia Sharma, John Y-J Shyy, Amanda Velazquez, Joseph E Ebinger, Susan Cheng","doi":"10.1161/ATVBAHA.124.322169","DOIUrl":"10.1161/ATVBAHA.124.322169","url":null,"abstract":"<p><strong>Background: </strong>Women experience excess cardiovascular risk compared with men in the setting of similar metabolic disease burden. We aimed to examine sex differences in the vascular response to various forms of metabolic stress.</p><p><strong>Methods: </strong>We conducted an observational study of 4299 adult participants (52% women, aged 59±13 years) of the National Health and Nutrition Examination Survey 2017 to 2018 cohort and 110 225 adult outpatients (55% women, aged 64±16 years) from the Cedars-Sinai Medical Center in 2019. We used natural splines to examine the association of systemic and organ-specific measures of metabolic stress including body mass index, hemoglobin A1c, hepatic FIB-4 (Fibrosis-4) score, and CKD-EPI estimated glomerular filtration rate with systolic blood pressure (SBP). Piecewise linear models were generated using normal value thresholds (body mass index <25 kg/m², hemoglobin A1c <5.7%, FIB-4 <1.3, and estimated glomerular filtration rate ≥90 mL/min), which approximated observed spline break points. The primary outcome was an increase in SBP in association with increase in each metabolic measure.</p><p><strong>Results: </strong>Women compared with men demonstrated larger magnitudes and an earlier onset of increase in SBP per increment increase across all metabolic stress measures. The slope of SBP increase per increment of each metabolic measure was greater for women than men particularly for metabolic measures within the normal range, with slope differences of 1.86 mm Hg per kg/m² of body mass index, 12.48 mm Hg per %hemoglobin A1c, 6.87 mm Hg per FIB-4 unit, and 0.44 mm Hg per mL/min decrement of estimated glomerular filtration rate in the National Health and Nutrition Examination Survey cohort (<i>P</i> difference <0.05 for all). Overall results were consistent in the Cedars-Sinai Medical Center cohort.</p><p><strong>Conclusions: </strong>Women exhibited greater SBP alteration in the setting of multiple types of metabolic stress, particularly in periods representing the transition from metabolic health to disease. These findings suggest potential benefit of early metabolic health interventions as part of efforts to mitigate vascular risks in both women and men.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"557-561"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514492","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":"Development of Zafirlukast Analogues for Improved Antithrombotic Activity Through Thiol Isomerase Inhibition.","authors":"Justine A Keovilay, Kaitlind C Howard, Kirk A Taylor, Sabeeya Khan, Sienna E Wurl, Melanie K Szahaj, Tanya Sage, Nishad Thamban Chandrika, Caixia Hou, Oleg V Tsodikov, Jonathan M Gibbins, Sylvie Garneau-Tsodikova, Daniel R Kennedy","doi":"10.1161/ATVBAHA.124.321579","DOIUrl":"10.1161/ATVBAHA.124.321579","url":null,"abstract":"<p><strong>Background: </strong>Thiol isomerases play essential and nonredundant roles in platelet activation, aggregation, and thrombus formation. Thiol isomerase inhibitors have the potential to overcome the 2 major drawbacks of current antithrombotic therapies, as they target both arterial and venous thrombosis without enhancing bleeding risks. Recently, a Food and Drug Administration-approved drug, zafirlukast (ZAF), was shown to be a promising pan-thiol isomerase inhibitor. The objective of this study is to develop analogues of ZAF with optimized thiol isomerase inhibition and antithrombotic activity.</p><p><strong>Methods: </strong>Thirty-five ZAF analogues were tested in an insulin turbidometric assay for thiol isomerase inhibition. Analogues were tested for platelet activation, aggregation, P-selectin expression, and laser-induced thrombosis in mice and compared with the parent compound.</p><p><strong>Results: </strong>Of the 35 analogues, 12 retained activity, with 1, compound 21, that demonstrated a greater potency than that of ZAF, 5 had a similar potency to that of ZAF, and 6 had a weaker potency. Analogues demonstrated inhibition of platelet aggregation and P-selectin expression as compared with ZAF, consistent with their potencies. ZAF and compound 21 were shown to be reversible inhibitors of thiol isomerases, and not cytotoxic to cultured, lung, liver, and kidney cells. Finally, in an in vivo assessment of thrombus formation, compound 21 was able to significantly inhibit thrombus formation without affecting bleeding times.</p><p><strong>Conclusions: </strong>A ZAF analogue, compound 21, with properties superior to those of ZAF was synthesized, demonstrating improved inhibition of platelet activation, aggregation, and thrombus formation as compared with the parent ZAF. This approach could yield a promising clinical candidate for treatment and prophylaxis of arterial and venous thrombosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e136-e149"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456717","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":"Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity.","authors":"Szumam Liu, Min Ma, Jun Qu, Joshua Muia, Zhijian Wu, Quintijn Bonnez, Karen Vanhoorelbeke, Liang Zheng, Xinyang Zhao, X Long Zheng","doi":"10.1161/ATVBAHA.124.322249","DOIUrl":"10.1161/ATVBAHA.124.322249","url":null,"abstract":"<p><strong>Background: </strong>ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13), primarily synthesized in hepatic stellate and endothelial cells, plays a pivotal role in regulation of hemostasis by proteolytic cleavage of von Willebrand factor. Severe deficiency of plasma ADAMTS13 activity may result in thrombotic thrombocytopenic purpura, a potentially fatal blood disorder. ADAMTS13 undergoes posttranslational modifications including glycosylation, citrullination, oxidation. The present study determines the impact of arginine methylation by PRMT1 (protein arginine methyltransferase 1) on ADAMTS13 secretion and function.</p><p><strong>Methods: </strong>Cell culture, recombinant protein, biochemical analysis, site-directed mutagenesis, and animal models were utilized.</p><p><strong>Results: </strong>An inhibition of arginine methylation by a type I methyl transferase PRMT inhibitor (MS023) in HEK (human embryonic kidney) 293 cells expressing recombinant ADAMTS13 and in mice results in a significant reduction of ADAMTS13 secretion, but the secreted ADAMTS13 shows an increased specific activity; conversely, an overexpression of PRMT1 in HEK-293 cells and in transgenic mice results in an increase of ADAMTS13 secretion, but the secreted ADAMTS13 exhibits a significantly reduced specific activity. The altered ADAMTS13 activity appeared to be related to its conformational changes. LC-MS/MS (liquid chromatography with tandem mass spectrometry) identified greater than100 arginine methylation events on purified recombinant ADAMTS13. Site-directed mutagenesis performed on 5 highly conserved methylation sites (R193, R498, R692, R1123, and R1206) identifies the critical role of R1206 in ADAMTS13 function. The ADAMTS13 R1206K variant exhibits a 4- to 5-fold increase of specific activity, likely resulting from an alleviation of allosteric inhibition.</p><p><strong>Conclusions: </strong>These results demonstrate the crucial role of arginine methylation in ADAMTS13 secretion and function. Our findings may shed new light on the mechanism of allosteric regulation of ADAMTS13, which may have a therapeutic implication.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"506-522"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11945488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405550","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":"SRSF4-Associated ca-circFOXP1 Regulates Hypoxia-Induced PASMC Proliferation by the Formation of R Loop With Host Gene.","authors":"Xinyue Song, Ya Xu, Mengnan Li, Xiaoyu Guan, Huiyu Liu, Jingya Zhang, Hanliang Sun, Cui Ma, Lixin Zhang, Xijuan Zhao, Xiaodong Zheng, Daling Zhu","doi":"10.1161/ATVBAHA.124.322026","DOIUrl":"10.1161/ATVBAHA.124.322026","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary hypertension (PH) is a rare and fatal disease, the pathological changes of which include pulmonary arterial smooth muscle cell (PASMC) proliferation, which is the pathological basis of pulmonary vascular remodeling. Studies have demonstrated that chromatin-associated circRNA can regulate a variety of biological processes. However, the role of chromatin-associated circRNA in the proliferation of PH remains largely unexplored. In this study, we aimed to identify the function and mechanism of chromatin-associated circRNA in PASMC proliferation in PH.</p><p><strong>Methods: </strong>The role of chromatin-associated circFOXP1 (ca-circFOXP1) was investigated in hypoxic mouse PASMCs and SuHX (Sugen5416+hypoxia) model mice through the use of antisense oligonucleotide knockdown and adeno-associated virus-mediated knockdown. Through bioinformatic sequence alignment, chromatin isolation by RNA purification, Cell Counting Kit 8, 5-ethynyl-2-deoxyuridine, Western blot, and other experiments, the function and mechanism of ca-circFOXP1 were verified.</p><p><strong>Results: </strong>The expression of ca-circFOXP1 was found to be significantly increased in SuHX model mice and hypoxic mouse PASMCs. Moreover, ca-circFOXP1 was found to regulate the level of the host protein FOXP1 (forkhead box protein 1) through the R loop, thereby influencing the phosphorylation activity of SMAD2 (SMAD family member 2) and, consequently, the proliferation of mouse PASMCs. It is noteworthy that the m6A modification was found to promote the formation of the R loop between ca-circFOXP1 and the host gene <i>FOXP1</i>, thereby regulating the expression of the host protein. Furthermore, we have identified that the splicing factor SRSF4 (serine/arginine rich splicing factor 4) can upregulate the expression of ca-circFOXP1 by splicing exons 6 and 9 of FOXP1 pre-mRNA.</p><p><strong>Conclusions: </strong>The results demonstrated that the splicing factor SRSF4 upregulated the expression of ca-circFOXP1, and m6A methylation promoted R-loop formation between ca-circFOXP1 and host genes, regulated the level of host protein FOXP1, and then affected the phosphorylation activity of SMAD2, mediating PASMC proliferation, leading to pulmonary vascular remodeling. These results provide a theoretical basis for further study of the pathological mechanisms of hypoxic PH and may provide certain insights.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e118-e135"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456720","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}