Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

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Linking Variability of Leukocyte Lipid Metabolism to Circulating Lipids, Lipoprotein Composition, and Cardiovascular Risk in the Finnish Adult Population. 芬兰成人白细胞脂质代谢变异性与循环脂质、脂蛋白组成和心血管风险的关系
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-19 DOI: 10.1161/ATVBAHA.125.322801
Iryna Hlushchenko, Siina Pamilo, Mohammad Majharul Islam, Iris Aino Karoliina Lähdeniemi, Max Tamlander, Samuli Ripatti, Simon Georg Pfisterer
{"title":"Linking Variability of Leukocyte Lipid Metabolism to Circulating Lipids, Lipoprotein Composition, and Cardiovascular Risk in the Finnish Adult Population.","authors":"Iryna Hlushchenko, Siina Pamilo, Mohammad Majharul Islam, Iris Aino Karoliina Lähdeniemi, Max Tamlander, Samuli Ripatti, Simon Georg Pfisterer","doi":"10.1161/ATVBAHA.125.322801","DOIUrl":"10.1161/ATVBAHA.125.322801","url":null,"abstract":"<p><strong>Background: </strong>Interindividual differences in outcomes of lipid-lowering therapy are well known. Here, we aimed to characterize how alterations in cellular lipid uptake, storage, and utilization pathways may contribute to different treatment outcomes.</p><p><strong>Methods: </strong>We performed an observational case-control biobank study quantifying leukocyte LDL (low-density lipoprotein) uptake and lipid storage with an automated multiplexed analysis pipeline for 133 statin recipients and 135 control subjects from the FINRISK 2012 study, a Finnish population survey on risk factors on chronic noncommunicable diseases. Individual cellular readouts as well as their combinations, which we called lipid trafficking scores, were then correlated to blood lipid values and health outcomes of the study participants.</p><p><strong>Results: </strong>Of individuals receiving high-intensity statin therapy, those with lower lipid trafficking scores displayed higher circulating concentrations of several proatherogenic lipoproteins and had higher odds for myocardial infarction and stroke when compared with the rest of the subjects with equivalent treatment. Most subjects with a poor lipid trafficking score did not reach low-density lipoprotein cholesterol target levels on statin monotherapy. Combining lipid trafficking score with a polygenic risk score for low-density lipoprotein cholesterol strengthened the association with a proatherogenic lipoprotein profile.</p><p><strong>Conclusions: </strong>Our results indicate that quantification of cellular lipid trafficking can aid in treatment selection and risk assessment in dyslipidemia.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1416-1431"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324369","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}
引用次数: 0
Single-Cell Multimodal Profiling Reveals a Novel CD26+ Fibroblast Subpopulation in Atherosclerosis-Brief Report. 单细胞多模态分析揭示动脉粥样硬化中一种新的CD26+成纤维细胞亚群。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-12 DOI: 10.1161/ATVBAHA.124.322370
Alexander C Bashore, Johana Coronel, Chenyi Xue, Lucie Y Zhu, Muredach P Reilly
{"title":"Single-Cell Multimodal Profiling Reveals a Novel CD26<sup>+</sup> Fibroblast Subpopulation in Atherosclerosis-Brief Report.","authors":"Alexander C Bashore, Johana Coronel, Chenyi Xue, Lucie Y Zhu, Muredach P Reilly","doi":"10.1161/ATVBAHA.124.322370","DOIUrl":"10.1161/ATVBAHA.124.322370","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis involves complex interactions between lipids, immune cells, vascular smooth muscle cells, and fibroblasts within the arterial wall. While significant advances in single-cell technologies have shed light on the roles of immune cells and vascular smooth muscle cells in plaque development, fibroblasts remain underexplored, leaving critical gaps in understanding their contributions to disease progression and plaque stability. Comprehensive characterization of fibroblast phenotypes in atherosclerosis is essential to unravel their diverse functions and to distinguish between subsets that may play protective versus pathogenic roles in the disease process.</p><p><strong>Methods: </strong>Here, we utilized cellular indexing of transcriptomes and epitopes by sequencing to comprehensively profile fibroblast diversity in a mouse model of atherosclerosis. Mice were fed an atherogenic diet for 0, 8, 19, and 26 weeks, representing distinct stages of disease progression, enabling a detailed phenotypic characterization of fibroblasts throughout the course of atherosclerosis development.</p><p><strong>Results: </strong>We identified 4 distinct fibroblast subpopulations, including a myofibroblast population closely resembling vascular smooth muscle cell-derived chondromyocytes. The proportions of these fibroblast subsets exhibited a modest decline as atherosclerosis progressed. Through multimodal analysis, we identified CD26 (cluster of differentiation) as a highly expressed and specific marker for one of these fibroblast subpopulations, distinguishing it from other subsets. Using a combination of flow cytometry and immunohistochemistry, we demonstrated that CD26<sup>+</sup> fibroblasts predominantly reside in the adventitia of healthy arteries. During atherosclerosis progression, these cells expand into the intima and primarily localize within the fibrous cap of the lesion.</p><p><strong>Conclusions: </strong>Our multiomic analysis highlights the phenotypic diversity and dynamic changes of fibroblasts during atherosclerosis progression. Among these, CD26<sup>+</sup> fibroblasts emerge as a distinct subpopulation that expands within atherosclerotic lesions and may play a critical role in promoting plaque stability through their migration into the fibrous cap.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1389-1397"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274119","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}
引用次数: 0
Hemodynamic Environments for the Progression of Carotid Stenosis: The NHO Carotid CFD Study. 颈动脉狭窄进展的血流动力学环境:NHO颈动脉CFD研究。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-12 DOI: 10.1161/ATVBAHA.125.322928
Shunichi Fukuda, Yuji Shimogonya, Aoi Watanabe, Yuko Yoshimoto, Setsurou Maruyama, Naohiro Yonemoto, Kazuha Fujiwara, Miyuki Fukuda, Akihiro Yasoda
{"title":"Hemodynamic Environments for the Progression of Carotid Stenosis: The NHO Carotid CFD Study.","authors":"Shunichi Fukuda, Yuji Shimogonya, Aoi Watanabe, Yuko Yoshimoto, Setsurou Maruyama, Naohiro Yonemoto, Kazuha Fujiwara, Miyuki Fukuda, Akihiro Yasoda","doi":"10.1161/ATVBAHA.125.322928","DOIUrl":"10.1161/ATVBAHA.125.322928","url":null,"abstract":"<p><strong>Background: </strong>Hemodynamic stress plays an important role in the development of atherosclerosis. It is difficult to sufficiently predict the progression of atherosclerosis and consequent stenosis based on known risk factors alone. This may be partly because the hemodynamic environments that promote stenosis progression remain unclear. The carotid bifurcation is the preferred site of atherosclerosis. In this prospective observational study, we sought to identify hemodynamic predictors of carotid stenosis progression.</p><p><strong>Methods: </strong>Computational fluid dynamics analysis was performed using arterial geometry and flow velocity specific to individual patients. Hemodynamic metrics were compared by multivariate analysis between the presence or absence of stenosis progression, using known risk factors as confounding factors.</p><p><strong>Results: </strong>A total of 545 patients were enrolled, and 361 stenotic arteries in 313 patients were analyzed, 38 of which had progressive stenosis. Among the carotid arteries with 30% to 55% area stenosis, those with stenosis progression had significantly lower time-averaged wall shear stress (WSS; odds ratio [OR], 0.078 [95% CI, 0.012-0.492]; <i>P</i>=0.0067) distal to the stenosis site and significantly higher oscillatory shear index (OR, 2.37 [95% CI, 1.17-4.82]; <i>P</i>=0.016). Among carotid arteries with 56% to 70% stenosis, those with stenosis progression had significantly higher time-averaged WSS (OR, 2.36 [95% CI, 1.19-4.72]; <i>P</i>=0.014) and transverse WSS (OR, 3.03 [95% CI, 1.45-6.34]; <i>P</i>=0.0033), a metric for multidirectional WSS disturbance, at the stenotic site and significantly higher transverse WSS (OR, 2.30 [95% CI, 1.20-4.42]; <i>P</i>=0.012) at the distal site. Arteries with 71% to 99% stenosis and stenosis progression had significantly higher oscillatory shear index (OR, 1.91 [95% CI, 1.05-3.47]; <i>P</i>=0.033) at the distal site.</p><p><strong>Conclusions: </strong>These data suggest the specific hemodynamic environments involved in the stenosis progression at bifurcation and that hemodynamic risk for stenosis progression differs depending on the degree of stenosis. Combining these hemodynamic predictors with known risk factors may allow a more accurate selection of cases at high risk of progression.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1448-1458"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274116","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}
引用次数: 0
Endocytosis, Transcytosis, and Retroendocytosis of HDL: Mechanisms, Pathophysiology, and Options for Clinical Exploitation. 高密度脂蛋白的内吞作用、胞吞作用和后内吞作用:机制、病理生理学和临床开发的选择。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-19 DOI: 10.1161/ATVBAHA.125.321546
Arnold von Eckardstein, Jerome Robert
{"title":"Endocytosis, Transcytosis, and Retroendocytosis of HDL: Mechanisms, Pathophysiology, and Options for Clinical Exploitation.","authors":"Arnold von Eckardstein, Jerome Robert","doi":"10.1161/ATVBAHA.125.321546","DOIUrl":"10.1161/ATVBAHA.125.321546","url":null,"abstract":"<p><p>For over 50 years, many cell types have been shown to internalize HDLs (high-density lipoproteins) as whole particles, either degrading or resecreting them. HDL endocytosis occurs through at least 4 pathways including (1) macropinocytosis, (2) a yet unknown HDL holoparticle receptor activated through signal transduction (eg, purinergic receptors), (3) cooperation between an HDL-binding protein and an endocytic receptor like the cubilin/megalin coreceptors, or (4) endocytic receptors for minor HDL components such as the apoE receptors. These manifold interactions of diverse proteins of HDL and cells, which we term HDL-synapses, are tissue-specific and may explain why the canonical HDL receptor SR-BI (scavenger receptor BI) mediates HDL endocytosis into endothelial and some cancer cells but not hepatocytes. Internalized HDLs have been localized in endosomes, lysosomes, and multivesicular bodies but the molecular mechanisms that traffic HDLs toward lysosomal degradation, immediate resecretion, or intermediate sequestration in multivesicular bodies are little understood. Despite the limited molecular understanding of endocytosis, transcytosis, and retroendocytosis of HDLs, several observations in humans and animal models highlight the relevance of cellular HDL trafficking for health and disease, as well as opportunities for diagnostic and therapeutic exploitation. In this review, we summarize the current understanding and knowledge gaps of endocytosis and cellular trafficking of HDLs on the molecular, pathophysiological, and clinical levels with a focus on liver, kidney, endothelium, macrophages, and intestine.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1346-1367"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324368","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}
引用次数: 0
FAM49B Fragmentation by Asparagine Endopeptidase Promotes Vascular Smooth Muscle Cell Migration in Atherogenesis. 天冬酰胺内肽酶对FAM49B的破坏促进血管平滑肌细胞在动脉粥样硬化中的迁移。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-26 DOI: 10.1161/ATVBAHA.125.322536
Xuying Xiang, Mengting Qin, Lei Nie, Xiaoqing Guo, Jiaojiao Chen, Dailiang Jiang, Zhentao Zhang, Ling Mao
{"title":"FAM49B Fragmentation by Asparagine Endopeptidase Promotes Vascular Smooth Muscle Cell Migration in Atherogenesis.","authors":"Xuying Xiang, Mengting Qin, Lei Nie, Xiaoqing Guo, Jiaojiao Chen, Dailiang Jiang, Zhentao Zhang, Ling Mao","doi":"10.1161/ATVBAHA.125.322536","DOIUrl":"10.1161/ATVBAHA.125.322536","url":null,"abstract":"<p><strong>Background: </strong>The migration of vascular smooth muscle cells (VSMCs) is critical for the development of atherosclerosis. However, the underlying molecular mechanisms are not completely understood. Here, we detected FAM49B (family with sequence similarity 49 member B) fragments in atherosclerotic plaques and identified their roles in VSMC migration and atherogenesis.</p><p><strong>Methods: </strong>Transgenic mice such as <i>Aep</i> (asparagine endopeptidase)<sup><i>-/-</i></sup>, <i>Aep</i><sup><i>-/-</i></sup><i>Apoe</i><sup><i>-/-</i></sup>, and VSMC-specific full-length FAM49B and FAM49B fragment overexpression by adenovirus gene transfer were used to determine the role of FAM49B fragments in atherosclerosis. In addition, the effects of compound 11, an AEP inhibitor, on the progression of atherosclerosis in <i>Apoe</i><sup><i>-/-</i></sup> mice were analyzed. FAM49B fragments were identified by mass spectrometry. Moreover, the expression of FAM49B fragments in atherosclerotic plaques from mice and patients was analyzed by immunofluorescence and immunoblotting.</p><p><strong>Results: </strong>The levels of FAM49B are increased in atherosclerotic lesions. Interestingly, FAM49B is cleaved by the cysteine protease AEP at residues N169 and N170, generating 2 fragments: FAM49B (1-169) and FAM49B (171-324). Both fragments are upregulated in VSMCs with the development of atherosclerotic plaques. The overexpression of full-length FAM49B inhibits the migration of human aortic VSMCs, whereas the overexpression of FAM49B fragments promotes VSMC migration. FAM49B fragments bind to Rac1 (Ras-related C3 botulinum toxin substrate 1) and increase its activity, thereby inducing actin polymerization and promoting cell migration. The overexpression of FAM49B fragments in mouse aortic VSMCs results in a higher atherosclerotic plaque burden, whereas the deletion of AEP blocks FAM49B fragmentation and decreases plaque size in mouse models of atherosclerosis. Furthermore, the administration of compound 11 blocked FAM49B fragmentation and alleviated atherosclerotic lesions.</p><p><strong>Conclusions: </strong>Our results indicate that AEP-derived FAM49B fragments facilitate Rac1-mediated VSMC migration and promote atherosclerosis progression. Inhibiting AEP-mediated FAM49B fragmentation may be a therapeutic strategy for atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e355-e373"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493817","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}
引用次数: 0
LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension. LncRNA-536和rna结合蛋白RBM25在肺动脉平滑肌细胞中的相互作用:肺动脉高压的意义
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-26 DOI: 10.1161/ATVBAHA.125.322734
Aatish Mahajan, Sivasankar Chandran, Ashok Kumar, Ling Chen, Navneet K Dhillon
{"title":"LncRNA-536 and RNA-Binding Protein RBM25 Interactions in Pulmonary Artery Smooth Muscle Cells: Implications in Pulmonary Hypertension.","authors":"Aatish Mahajan, Sivasankar Chandran, Ashok Kumar, Ling Chen, Navneet K Dhillon","doi":"10.1161/ATVBAHA.125.322734","DOIUrl":"10.1161/ATVBAHA.125.322734","url":null,"abstract":"<p><strong>Background: </strong>In this study, we define the mechanistic association between long noncoding RNA: ENST00000495536 (lnc-536) and transcription factor HOXB13 (homeobox B13) in mediating proproliferative smooth muscle phenotype associated with pulmonary hypertension.</p><p><strong>Methods: </strong>In vitro knockdown or knockin, along with RNA pull-down and immunoprecipitation studies, were used to evaluate the role of lnc-536 and HOXB13 in regulating pulmonary arterial smooth muscle cell (PASMCs) phenotype. The in vivo role was determined by injecting lnc-536 antisense oligos in pulmonary hypertensive rats.</p><p><strong>Results: </strong>Increased levels of lnc-536 promote the proliferative phenotype of PASMCs by downregulating the expression of the tumor suppressor: HOXB13. Knockdown of lnc-536 and overexpression of HOXB13 in proliferative PASMCs resulted in increased expression of VGLL4 (vestigial-like family member 4), a negative regulator of Hippo and Wnt (Wingless-related integration site) signaling pathways, with a corresponding decrease in TEAD4 (TEA domain family member 1) expression. The lnc-536 pull-down assay and RNA-immunoprecipitation demonstrated the interactions of lnc-536 with RBP (RNA-binding protein): RBM25 (RNA-binding motif 25) and direct interactions of RBM25 with SFPQ (splicing factor proline/glutamine-rich), a transcriptional regulator that has a binding motif on HOXB13. The knockdown of RBM25 in the hyperproliferative PASMCs resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Furthermore, the increased levels of lnc-536 and decreased levels of HOXB13 were observed in PASMCs from idiopathic pulmonary hypertension patients but not in cells from familial pulmonary hypertension patients. We confirmed that lnc-536 contributes to the RBM25-mediated remodeling of the SFPQ-HOXB13 complex in the idiopathic PAH-PASMCs as well. Finally, in vivo inhibition of lnc-536 using GapmeRs (Gapmer antisense oligonucleotides) in Sugen-hypoxia and HIV-transgenic pulmonary hypertension rats prevented the increase in right ventricular systolic pressure, right ventricular hypertrophy/fibrosis, and pulmonary vascular remodeling with a parallel increase in HOXB13 expression in rat PASMCs.</p><p><strong>Conclusions: </strong>Lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to a decrease in HOXB13 expression and hyperproliferation of smooth muscle cells by potentially regulating Wnt and Hippo signaling associated with PAH development.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e374-e391"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493820","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}
引用次数: 0
Antisense Oligonucleotide Targeting Sortilin Reduces Vascular Calcification in Mice in a Sex-Dependent Manner. 针对Sortilin的反义寡核苷酸以性别依赖的方式减少小鼠血管钙化。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-12 DOI: 10.1161/ATVBAHA.124.321999
Adrien Lupieri, Dakota Becker-Greene, Thanh-Dat Le, Marina M Roschel, Prabhash K Jha, Abhijeet R Sonawane, Adam Mullick, Sotirios Tsimikas, Shiori Kuraoka, Sasha A Singh, Masanori Aikawa, Elena Aikawa
{"title":"Antisense Oligonucleotide Targeting Sortilin Reduces Vascular Calcification in Mice in a Sex-Dependent Manner.","authors":"Adrien Lupieri, Dakota Becker-Greene, Thanh-Dat Le, Marina M Roschel, Prabhash K Jha, Abhijeet R Sonawane, Adam Mullick, Sotirios Tsimikas, Shiori Kuraoka, Sasha A Singh, Masanori Aikawa, Elena Aikawa","doi":"10.1161/ATVBAHA.124.321999","DOIUrl":"10.1161/ATVBAHA.124.321999","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerotic calcification is a complex pathological process associated with an increased risk of cardiovascular events. Despite extensive research, this disorder has no effective therapeutic strategies. In this study, we evaluated the therapeutic potential of silencing Sort (sortilin) expression in vivo using antisense oligonucleotide (ASO-Sort1) to reduce the development of atherosclerosis and associated calcification.</p><p><strong>Methods: </strong>Male and female <i>Ldlr</i><sup>-/-</sup> (low-density lipoprotein receptor knock-out) mice were fed a high-fat diet and treated with ASO-Sort1 for 15 weeks. After ASO-Sort1 treatment, we evaluated atherosclerotic lesion formation and calcification through molecular imaging and histological techniques. The levels of plasma lipid and inflammatory molecules were determined. Unbiased liquid chromatography-mass spectrometry-based proteomics of aortic arches was conducted to investigate the sex-specific regulation in ASO-Sort1-treated mice. To validate our in vivo findings, we conducted in vitro experiments to examine whether β-estradiol treatment of mouse smooth muscle cells promotes calcification independently of Sort.</p><p><strong>Results: </strong>ASO targeted primarily arterial smooth muscle cells, leading to a comparable reduction of aortic Sort1 expression by ≈57% in males and 52% in females. Although ASO-Sort1 did not affect the size of atherosclerotic lesions, it significantly reduced necrotic core development by 60% in male and 40% in female mice. In addition, it prevented aortic calcification by >50% only in male mice. Furthermore, proteome analysis revealed that while this treatment reduced vesicular trafficking, immune system, and extracellular matrix organization pathways in both male and female mice, it reduced autophagy-related processes specifically in males. In vitro results indicated that β-estradiol promotes calcification in smooth muscle cells treated with ASO-Sort1 by altering autophagy.</p><p><strong>Conclusions: </strong>Targeting Sort using antisense technology is effective in preventing vascular calcification in male mice. This unexpected outcome highlighted a novel sex-dependent discrepancy of the calcification pathway implicating the alteration of autophagy by β-estradiol and Sort.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1398-1415"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274115","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}
引用次数: 0
Direct Interleukin-6 Inhibition Blunts Arterial Thrombosis by Reducing Collagen-Mediated Platelet Activation. 直接抑制白介素-6通过减少胶原介导的血小板活化来钝化动脉血栓形成。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-19 DOI: 10.1161/ATVBAHA.125.322533
Stefano Ministrini, Luca Liberale, Yustina M Puspitasari, Jiaying Han, Kilian Kirmes, Leonhard Paul Unkelbach, Amedeo Tirandi, Rebecca Niederberger, Susan Bengs, Jürg H Beer, Fabrizio Montecucco, Peter Libby, Thomas F Lüscher, Dario Bongiovanni, Giovanni G Camici
{"title":"Direct Interleukin-6 Inhibition Blunts Arterial Thrombosis by Reducing Collagen-Mediated Platelet Activation.","authors":"Stefano Ministrini, Luca Liberale, Yustina M Puspitasari, Jiaying Han, Kilian Kirmes, Leonhard Paul Unkelbach, Amedeo Tirandi, Rebecca Niederberger, Susan Bengs, Jürg H Beer, Fabrizio Montecucco, Peter Libby, Thomas F Lüscher, Dario Bongiovanni, Giovanni G Camici","doi":"10.1161/ATVBAHA.125.322533","DOIUrl":"10.1161/ATVBAHA.125.322533","url":null,"abstract":"<p><strong>Background: </strong>Recent clinical trials demonstrated a reduction in biomarkers of thrombosis and inflammation in patients with very high cardiovascular risk treated with the anti-IL-6 (interleukin 6) monoclonal antibody ziltivekimab. However, if and how direct IL-6 inhibition exerts antithrombotic effects remains unknown. This translational project aimed to investigate the effect of direct IL-6 inhibition on experimental arterial thrombus formation and its underlying cellular mechanisms.</p><p><strong>Methods: </strong>Three-month-old C57BL/6J male and female mice received very low dose lipopolysaccharide for 4 weeks; in addition to lipopolysaccharide, during the fourth week, mice were randomized to receive either anti-mouse IL-6 monoclonal antibody 200 μg or IgG1 isotype control. Thrombosis of the right common carotid artery was induced by endothelial-targeted laser injury. Coagulation factors and platelet reactivity were assessed in treated mice and controls. Platelets were isolated from whole blood and their reactivity to different chemical stimuli was measured by fluorescence-activated cell sorting. Additionally, whole blood samples from patients with a history of percutaneous coronary intervention were incubated ex vivo with either ziltivekimab biosimilar or IgG1 isotype control. Platelet reactivity at rest and in response to diverse chemical stimuli was quantified by fluorescence-activated cell sorting.</p><p><strong>Results: </strong>Mice with low-grade chronic inflammation treated with anti-IL-6 monoclonal antibody displayed significantly blunted thrombus formation, without any significant difference in coagulation factors. Ex vivo stimulation with Collagen-rP (collagen-related peptide) significantly activated platelets isolated from control mice but not those obtained from mice treated with anti-IL-6 monoclonal antibody. Similarly, platelet reactivity from patients with previous percutaneous coronary intervention fell significantly after ex vivo treatment with ziltivekimab biosimilar.</p><p><strong>Conclusions: </strong>Direct IL-6 inhibition blunts thrombus formation by reducing collagen-induced platelet activation. These findings offer a potential mechanistic explanation for the results observed in the RESCUE trial and support the rationale of the ongoing ZEUS trial (Ziltivekimab Cardiovascular Outcome Study).</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1432-1439"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324367","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}
引用次数: 0
Remembering Dr Janet T. Powell. 记住珍妮特·鲍威尔博士。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-07-23 DOI: 10.1161/ATVBAHA.125.323274
Ann Marie Schmidt, Robert A Hegele
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引用次数: 0
Association Between the Amount of Carotid Perivascular Adipose Tissue and Prior Ischemic Stroke: An MR Imaging Study. 磁共振成像测量颈动脉血管周围脂肪组织的数量:缺血性卒中风险的潜在指标。
IF 7.4 1区 医学
Arteriosclerosis, Thrombosis, and Vascular Biology Pub Date : 2025-08-01 Epub Date: 2025-06-05 DOI: 10.1161/ATVBAHA.125.322687
Shuwan Yu, Ran Huo, Xueyi Chen, Xiaowei Song, Huiyu Qiao, Zihan Ning, Huimin Xu, Dandan Yang, Decheng Meng, Ning Xu, Zixuan Lin, Ying Liu, Xihai Zhao
{"title":"Association Between the Amount of Carotid Perivascular Adipose Tissue and Prior Ischemic Stroke: An MR Imaging Study.","authors":"Shuwan Yu, Ran Huo, Xueyi Chen, Xiaowei Song, Huiyu Qiao, Zihan Ning, Huimin Xu, Dandan Yang, Decheng Meng, Ning Xu, Zixuan Lin, Ying Liu, Xihai Zhao","doi":"10.1161/ATVBAHA.125.322687","DOIUrl":"10.1161/ATVBAHA.125.322687","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to explore the association between the amount of carotid artery perivascular adipose tissue (PVAT) quantified by magnetic resonance imaging and prior cerebral infarction.</p><p><strong>Methods: </strong>A total of 139 patients (mean age, 64.4±8.2 years; 112 men) with moderate-to-severe atherosclerotic stenosis referred to carotid endarterectomy were included and underwent multicontrast magnetic resonance vessel wall and brain imaging. The amount of carotid artery PVAT with vulnerable plaque components on magnetic resonance images of each patient was quantitatively analyzed, and the measurements included the average PVAT area, PVAT area index, and PVAT volume index. The amount measurements of PVAT at slices with vulnerable plaque between patients with and without prior cerebral infarction were compared. Logistic regression analyses were conducted to determine the association between the amount measurements of PVAT and prior cerebral infarction.</p><p><strong>Results: </strong>Patients with prior cerebral infarction showed significantly higher PVAT area, PVAT area index, and PVAT volume index compared with those without (all <i>P</i><0.01). The carotid PVAT area (odds ratio [OR], 1.015 [95% CI, 1.003-1.028]; <i>P</i>=0.018), PVAT area index (OR, 2.051 [95% CI, 1.084-3.880]; <i>P</i>=0.027), and PVAT volume index (OR, 2.864 [95% CI, 1.343-6.108]; <i>P</i>=0.006) on the index side were significantly associated with prior cerebral infarction in univariate logistic regression. After adjusting for clinical confounding factors and plaque features, the associations between carotid PVAT area (OR, 1.028 [95% CI, 1.008-1.048]; <i>P</i>=0.006), PVAT area index (OR, 3.587 [95% CI, 1.451-8.870]; <i>P</i>=0.006), and PVAT volume index (OR, 6.053 [95% CI, 2.048-17.889]; <i>P</i>=0.001) and prior cerebral infarction remained statistically significant.</p><p><strong>Conclusions: </strong>The amount of PVAT in carotid artery with vulnerable plaques is independently associated with prior cerebral infarction and may, therefore, be related to the occurrence of ischemic stroke.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1440-1447"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224167","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}
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