Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Correction to: CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling.","authors":"Lingfeng Qin, Haifeng Zhang, Busu Li, Quan Jiang, Francesc Lopez, Wang Min, Jenny Huanjiao Zhou","doi":"10.1161/ATV.0000000000000190","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000190","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 9","pages":"e469"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940396","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":"Novel Function for Endothelial Protease-Activated Receptors in Modulating Insulin Receptor Activity With Implications for Diabetes.","authors":"Rahul Rajala, Courtney T Griffin","doi":"10.1161/ATVBAHA.125.323140","DOIUrl":"10.1161/ATVBAHA.125.323140","url":null,"abstract":"<p><strong>Background: </strong>Thrombin, a serine protease with increased activity in people with diabetes, signals through PAR (protease-activated receptor) 1 and 4 on endothelial cells (ECs). On these cells, PAR1 is a high-expressing, high-affinity, low-potency thrombin receptor, whereas PAR4 is a low-expressing, low-affinity, high-potency receptor. This study aims to determine how endothelial PARs influence diabetic pathology, thereby providing deeper insights into the roles and relationships between these receptors.</p><p><strong>Methods: </strong>We generated mice with inducible deletion of <i>Par1/Par4</i> in ECs (<i>Par1/4</i>^<i>iECko</i>) and induced diabetes with streptozotocin treatment. Blood glucose and insulin levels were assessed after streptozotocin administration. In addition, we measured insulin and glucose tolerance in <i>Par1/4</i>^<i>iECko</i> mice. Lastly, we measured how the loss of endothelial PARs in cultured primary ECs affected IR (insulin receptor) activity/phosphorylation, and insulin transcytosis.</p><p><strong>Results: </strong>While studying the roles of endothelial PAR1/4 in diabetic pathology, we found that <i>Par1/4</i>^<i>iECko</i> mice displayed increased insulin sensitivity and were protected against streptozotocin-induced diabetes. Concordantly, we found that cultured primary ECs with PAR1/4 deficiency exhibited increased basal activity and phosphorylation of IR in a Gα_q/protein kinase C-dependent manner, as well as enhanced insulin transcytosis. This elevated IR activity correlated with reduced activity of PTP1B (protein tyrosine phosphatase 1B), a negative regulator of IR. Lastly, <i>Par1/4</i>^<i>iECko</i> mice with additional deletion of 1 allele of the endothelial IR gene demonstrated restoration of diabetic phenotypes after streptozotocin treatment, indicating that insulin sensitivity in <i>Par1/4</i>^<i>iECko</i> mice was driven by heightened IR activity in ECs.</p><p><strong>Conclusions: </strong>These findings establish a novel link between endothelial PAR signaling and insulin sensitivity, underscoring the critical role of ECs in metabolic homeostasis and identifying a potential therapeutic target for diabetes.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1648-1663"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752191","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":"Circular RNA Profiling Identifies <i>circ5078</i> as a <i>BMPR2</i>-Derived Regulator of Endothelial Proliferation and Stress Responses.","authors":"M Martin VandenBroek, Mackenzie C Sharp, Patrick Thompson, Emmanuel Fagbola, Douglas Quilty, Jeffrey D Mewburn, Anne L Theilmann, Kimberly J Dunham-Snary, Anna R Hemnes, Joy D Cogan, Eric D Austin, Rizwan Hamid, Stephen L Archer, Neil Renwick, Mark L Ormiston","doi":"10.1161/ATVBAHA.124.322455","DOIUrl":"10.1161/ATVBAHA.124.322455","url":null,"abstract":"<p><strong>Background: </strong>The <i>BMPR2</i> gene encodes the BMPR-II (bone morphogenetic protein receptor type-II) and is a known regulator of endothelial proliferation, apoptosis, and translational stress responses. While these effects are generally attributed to the actions of BMPR-II protein, we used circular RNA profiling to identify <i>circ3218</i> and <i>circ5078</i> as new <i>BMPR2</i>-derived functional RNAs.</p><p><strong>Methods: </strong>Circular RNAs were profiled by ultradeep RNA sequencing of human pulmonary artery endothelial cells. Novel <i>BMPR2</i>-derived circular RNAs were assessed for their effects on endothelial proliferation, apoptosis, and translational stress responses in human pulmonary artery endothelial cells and endothelial cells from patients with pulmonary arterial hypertension with heterozygous loss-of-function <i>BMPR2</i> mutations. <i>circ5078</i> to linear <i>BMPR2</i> mRNA ratios were quantified in cultured lymphocytes from patients with pulmonary arterial hypertension with <i>BMPR2</i> mutations versus unaffected mutation carriers.</p><p><strong>Results: </strong>Depletion of <i>circ3218</i> enhanced human pulmonary artery endothelial cell apoptosis, whereas <i>circ5078</i> silencing increased proliferation. Enhanced proliferation with <i>circ5078</i> depletion was eliminated by cosilencing of <i>circ5078</i> with either linear <i>BMPR2</i> mRNA or the stress granule protein, Caprin-1, indicating a potential interdependence of <i>BMPR2</i> transcripts in the regulation of endothelial function. Patients with pulmonary arterial hypertension with <i>BMPR2</i> mutations exhibited increased <i>circ5078</i> to linear <i>BMPR2</i> mRNA ratios, alongside impaired stress responses in patient endothelial cells that were deficient in linear <i>BMPR2</i> transcripts but not <i>circ5078</i>. <i>circ5078</i> depletion enhanced stress responses in human pulmonary artery endothelial cells and rescued stress granule formation in patient endothelial cells, independent of BMPR-II protein levels. Assessment of translational regulation by polysome profiling did not identify any impact of linear or circular <i>BMPR2</i> transcript loss on global protein synthesis or stress-induced eIF2α (eukaryotic initiation factor 2α) phosphorylation but did identify the enhanced translational efficiency of select nuclear-encoded mitochondrial ribosome proteins with <i>circ5078</i> depletion, offering a link between mitochondrial function and the <i>circ5078</i>-deficient endothelial phenotype.</p><p><strong>Conclusions: </strong>The identification of <i>circ3218</i> and <i>circ5078</i> as novel <i>BMPR2</i>-derived gene products reveals interdependent roles for coding and noncoding <i>BMPR2</i> transcripts as regulators of endothelial function.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1546-1561"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793346","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":"At Lats: Flow Has Come Along.","authors":"Jules D Allbritton-King, Guillermo García-Cardeña","doi":"10.1161/ATVBAHA.125.323214","DOIUrl":"10.1161/ATVBAHA.125.323214","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1543-1545"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793344","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":"Myeloid Protein Kinase C Epsilon: A New Marker for Plaque Stability?","authors":"Anish A Kanhai, Ilze Bot","doi":"10.1161/ATVBAHA.125.323345","DOIUrl":"10.1161/ATVBAHA.125.323345","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1516-1518"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793350","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":"Lamin A/C Expression in Hematopoietic Cells Declines During Human Aging and Constrains Atherosclerosis in Mice.","authors":"Marta Amorós-Pérez, Alberto Del Monte-Monge, Pilar Gonzalo, María J Andrés-Manzano, Cristina Rius, Víctor Fanjul, Cristina González-Gómez, Guillermo Moreno, Alberto Benguría, Ana Dopazo, Fátima Sánchez-Cabo, Carlos Torroja, Fernando Martínez de Benito, Bianca Calì, Pablo Vargas, Carlos Silvestre-Roig, José M González-Granado, Héctor Bueno, José J Fuster, Vicente Andrés","doi":"10.1161/ATVBAHA.124.322893","DOIUrl":"10.1161/ATVBAHA.124.322893","url":null,"abstract":"<p><strong>Background: </strong>Aging is the primary risk factor for atherosclerosis, a degenerative process regulated by immune cells and the leading cause of death worldwide. Previous studies on premature aging syndromes have linked atherosclerosis to defects in A-type lamins, key nuclear envelope components. However, whether these defects influence atherosclerosis during normal aging remains unexplored. Here, we examined how aging affects lamin A/C expression in circulating leukocytes and investigated the impact of manipulating their expression in hematopoietic cells on their function and atherosclerosis progression.</p><p><strong>Methods: </strong>Flow cytometry assessed lamin A/C expression in human circulating leukocytes. Bone marrow from donor mice was transplanted into lethally irradiated, <i>Ldlr</i>^<i>-/-</i>-deficient mice to study leukocyte extravasation into the vessel wall via intravital microscopy in the cremaster muscle, and high-fat-diet-induced atherosclerosis via Oil Red O staining of the aorta and carotid arteries. Single-cell RNA sequencing of the aorta was conducted to identify transcriptional changes associated with hematopoietic cell lamin A/C gain-of-function or loss-of-function.</p><p><strong>Results: </strong>Human aging is associated with lower levels of lamin A/C expression in blood-borne leukocytes. To evaluate the functional relationship between hematopoietic lamin A/C expression and atherosclerosis development, we used <i>Lmna</i>-null mice and <i>Lmna</i>^<i>tg</i> mice, the latter being the first in vivo model of lamin A gain-of-function. Transplanting lamin A/C-deficient bone marrow into <i>Ldlr</i>^<i>-/-</i> mice increased leukocyte extravasation into the vessel wall and accelerated atherosclerosis. Conversely, transplantation of bone marrow overexpressing lamin A into <i>Ldlr</i>^<i>-/-</i> receptor mice reduced leukocyte extravasation and atherosclerosis. Single-cell RNA sequencing of atherosclerotic mouse aorta revealed that alterations to hematopoietic cell lamin A/C expression primarily modify the transcriptome of immune cell populations and endothelial cells, affecting their functionality.</p><p><strong>Conclusions: </strong>We suggest that the age-related decline in lamin A/C expression in blood-borne immune cells contributes to increased leukocyte extravasation and atherosclerosis, highlighting lamin A/C as a novel regulator of age-related atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1616-1635"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551796","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":"Developmental Endothelial Locus 1 Reduces Traumatic Brain Injury-Induced Endotheliopathy and Dysregulated Coagulation in Mice.","authors":"Xiaoyang Zhang, Yuyang Miao, Tianrui Ma, Lujia Tang, Min Wang, Yafan Liu, Zijian Zhou, Yuan Zhou, Li Liu, Guili Yang, Perumal Thiagarajan, Jessica C Cardenas, Charles E Wade, Yang Li, Jianlong Men, Min Li, Jianning Zhang, Jing-Fei Dong, Zilong Zhao","doi":"10.1161/ATVBAHA.125.322515","DOIUrl":"10.1161/ATVBAHA.125.322515","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) induces endothelial injury (endotheliopathy) that disrupts the vascular barrier to cause cerebral hemorrhage and inflammation and allows the release of extracellular vesicles (EVs) from injured brain cells into the circulation. These EVs are highly procoagulant, causing a systemic hypercoagulable state that rapidly turns into consumptive coagulopathy. Protecting endothelial integrity and removing procoagulant EVs is, therefore, critical to preventing secondary cerebral and extracranial injuries from TBI.</p><p><strong>Methods: </strong>We measured plasma Del-1 (developmental endothelial locus 1) levels in severe TBI mouse models and administered exogenous Del-1 pre-TBI or post-TBI to assess its effects on endotheliopathy, coagulopathy, and outcomes. Mechanistic studies involved administering exogenous Del-1 to TBI mice, followed by EV-scavenging analysis, and evaluating adhesion and apoptosis in Del-1-treated cultured endothelial cells, with key findings validated in both wild-type and Del-1-deficient mice.</p><p><strong>Results: </strong>Plasma levels of Del-1 were reduced by 69% in mice subjected to severe TBI. Exogenous Del-1, given as either a preconditioning or a therapeutic agent, prevented mice with severe TBI from developing local and systemic endotheliopathy and coagulopathy, improving their outcomes. Del-1 protected TBI mice by scavenging anionic phospholipid-expressing EVs, including extracellular mitochondria from the circulation, by promoting endothelial cell adhesion and survival to protect endothelial integrity in wild-type and Del-1-deficient mice subjected to severe TBI.</p><p><strong>Conclusions: </strong>This study demonstrates the importance of reducing anionic phospholipid-expressing EVs for TBI resuscitation and identifies Del-1 as a potential therapeutic agent to reduce EV-induced endotheliopathy and coagulopathy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e454-e466"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697540","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":"Plasma <i>N</i>-Glycan Signatures Are Associated With a First Event of Venous Thromboembolism.","authors":"Ruifang Li-Gao, Marco R Bladergroen, Frits R Rosendaal, Manfred Wuhrer, Astrid van Hylckama Vlieg","doi":"10.1161/ATVBAHA.125.323205","DOIUrl":"10.1161/ATVBAHA.125.323205","url":null,"abstract":"<p><strong>Background: </strong>Coagulation factors play important roles in the pathophysiology of venous thromboembolism (VTE), and most of them are glycoproteins, that is, proteins containing glycans attached. Although the connection between glycosylation and coagulation factors seems obvious, the association between glycosylation and VTE risk remains unexplored. We aimed to elucidate the association between <i>N</i>-glycans in plasma and VTE risk in the MEGA study (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis), a case-control study aiming to identify risk factors for VTE.</p><p><strong>Methods: </strong>The total plasma <i>N</i>-glycomes of 491 VTE cases with a first idiopathic VTE and 472 controls were analyzed using a robust mass spectrometry platform. In total, 91 <i>N</i>-glycans were measured. The association between each <i>N</i>-glycan and the risk of a first VTE was analyzed with logistic regression models, adjusted for potential confounders. In addition, we also examined the associations between VTE-associated <i>N</i>-glycans as well as glycosylation features and VTE-associated coagulation factors with linear regression models.</p><p><strong>Results: </strong>In the analysis, 466 idiopathic VTE cases and 454 controls were included. We found that fucosylation of complex-type glycans and the presence of more antennae in glycan structures were associated with an increased risk of VTE. Conversely, monoantennary and diantennary complex-type glycans, as well as oligomannose-type glycans, were associated with a reduced risk of VTE. The associations between glycan features and VTE risk were partially supported by their relationships with procoagulant factors.</p><p><strong>Conclusions: </strong>We demonstrated the relevance of plasma <i>N</i>-glycan signatures in the risk of a first VTE. Plasma <i>N</i>-glycome holds a strong potential for VTE risk stratification.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1693-1703"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793352","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":"Association of Serum Thromboinflammatory Biomarkers With Atherosclerotic Plaques and Burden in a Community-Based Population.","authors":"Baoshan Qiu, Xueli Cai, Lebo Zhou, Xuan Wang, Shan Li, Nan Wang, Lingling Jiang, Jing Jing, Tiemin Wei, Yongjun Wang, Yuesong Pan, Yilong Wang","doi":"10.1161/ATVBAHA.125.322586","DOIUrl":"10.1161/ATVBAHA.125.322586","url":null,"abstract":"<p><strong>Background: </strong>The pathogenesis of atherosclerosis involves complex mechanisms, with inflammation playing a central role. Thromboinflammation may contribute to its development and progression. We investigated the association between circulating thromboinflammatory biomarkers and atherosclerotic plaques.</p><p><strong>Methods: </strong>Participants aged 50 to 75 years from the baseline survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included. Serum levels of thromboinflammatory biomarkers (sGPVI [soluble glycoprotein VI]; sADAMTS13 [soluble a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13]; and sP-selectin) were assessed by ELISA and Luminex assays and categorized into quartiles based on their empirical distribution within the study population. Eligible participants underwent imaging using computed tomography angiography and magnetic resonance imaging for coronary atherosclerosis, intracranial atherosclerosis, and extracranial atherosclerosis, respectively.</p><p><strong>Results: </strong>A total of 3019 participants (mean age, 61.20±6.68 years; 46.47% male) were analyzed. After multivariable adjustment, participants in the fourth quartile of sGPVI levels had higher odds of coronary atherosclerotic plaque burden (common odds ratio, 1.42 [95% CI, 1.14-1.76]; <i>P</i>=0.0017). Conversely, those in the highest sADAMTS13 quartile had lower odds of coronary plaques (odds ratio, 0.75 [95% CI, 0.60-0.93]; <i>P</i>=0.0094), as well as reduced coronary plaque burden, including segment involvement score (common odds ratio, 0.75 [95% CI, 0.61-0.93]; <i>P</i>=0.0087) and segment stenosis score (common odds ratio, 0.75 [95% CI, 0.61-0.93]; <i>P</i>=0.0086). No significant associations were observed between sGPVI or sADAMTS13 levels and intracranial or extracranial atherosclerosis. Likewise, after multivariable adjustment, no significant associations were observed between sP-selectin (soluble P-selectin) levels and coronary, intracranial, or extracranial atherosclerosis.</p><p><strong>Conclusions: </strong>In our study, serum sADAMTS13 levels showed a negative association with both the presence and burden of coronary atherosclerosis, while sGPVI levels showed a positive association with the burden of coronary atherosclerosis. However, significant associations between the level of thromboinflammatory biomarkers, intracranial atherosclerosis, and extracranial atherosclerosis were not found.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1672-1682"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551795","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":"LDL-Bound PCSK9 Has a Slower Clearance Kinetic and Higher Use for HSPGs Than Free-PCSK9-Brief Report.","authors":"Silvia Cecilia Pacheco-Velázquez, Carlota Oleaga, Bastian Ramms, Joshua Hay, Paul A Mueller, Ester López-Aguilar, Joshua Miles, Ryan N Porell, Chelsea Cheng, Kamil Godula, Hagai Tavori, Philip L S M Gordts, Sergio Fazio, Nathalie Pamir","doi":"10.1161/ATVBAHA.124.322334","DOIUrl":"10.1161/ATVBAHA.124.322334","url":null,"abstract":"<p><strong>Background: </strong>Hepatic heparan sulfate proteoglycans (HSPGs) accelerate the clearance of PCSK9 (proprotein convertase subtilisin/kexin type 9). We tested the hypothesis that free- and LDL (low-density lipoprotein)-bound PCSK9 forms have different HSPG-mediated clearance kinetics.</p><p><strong>Methods: </strong>Metabolic and turnover studies were performed after administration of free- and LDL-bound PCSK9 to 2 HSPG knockout mouse models: (1) Global knockout of syndecan-1 (<i>Sdc1</i>^-/^-), an HSPG involved in hepatic triglyceride clearance; and (2) hepatocyte-specific knockout of heparan sulfate N-deacetylase/N-sulfotransferase <i>(AlbCre</i>^<i>+</i><i>Ndst1</i>^<i>f/f</i>).</p><p><strong>Results: </strong>The clearance of both free- and LDL-bound PCSK9 followed a 2-phase decay behavior comprising a fast and a slow phase. The more notorious effect of HSPG deletion was on the slow phase: the clearance of free-PCSK9 was faster in <i>Sdc1</i>^<i>-/</i>^<i>-</i> mice (t_1/2,slow [half-life on the slow phase] 13.5±1.5 minutes; <i>P</i>=0.0305) than in wild-type (t_1/2,slow 28.8±4.2 minutes) and <i>AlbCre</i>^<i>+</i><i>Ndst1</i>^<i>f/f</i> mice (t_1/2,slow 32.7±4.9 minutes). The clearance of LDL-bound PCSK9 was slower yet not statistically significant in <i>Sdc1</i>^<i>-/</i>^<i>-</i> mice (t_1/2,slow 111.2±21.6 minutes) than in wild-type (t_1/2,slow 52±6.4 minutes) and <i>AlbCre</i>^<i>+</i><i>Ndst1</i>^<i>f/f</i> mice (t_1/2,slow 39.55±2.96 minutes). However, the area under the curve showed a delayed clearance of LDL-bound PCSK9 in <i>Sdc1</i>^<i>-/</i>^<i>-</i> mice (44 576±2435 min×ng, <i>P</i>=0.004) but not in <i>AlbCre</i>^<i>+</i><i>Ndst1</i>^<i>f/f</i> (34 738±3721 min×ng, <i>P</i>=0.578) mice compared with wild-type (30 865±1907 min×ng). Hepatic <i>Ndst1</i>-deficiency did not alter hepatic PCSK9 or LDLR (LDL receptor) expression.</p><p><strong>Conclusions: </strong>The clearance rate of plasma LDL-bound PCSK9 is slower than the clearance rate of its free form. The HSPG syndecan-1 modestly contributes to PCSK9 clearance through an LDLR-independent pathway.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1565-1573"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551797","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}