Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Potential Roles of SNX17, Rab11, and Rab5 in LDLR Recycling.","authors":"Xiaofei Zhao, Shiyin Long, Meiqi Zhu, Hong Hao, Ying Liao, Caiping Zhang, Zhenguo Liu","doi":"10.1161/ATVBAHA.125.322498","DOIUrl":"10.1161/ATVBAHA.125.322498","url":null,"abstract":"<p><p>Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality globally. Elevated levels of serum LDL-C (low-density lipoprotein cholesterol) represent a significant risk factor for atherosclerosis. LDLR (low-density lipoprotein receptor) plays a critical role in LDL-C uptake and clearance, with its recycling to the cell surface being essential for maintaining LDLR availability. However, the molecular mechanisms underlying LDLR homeostasis and recycling remain poorly defined. SNX (sorting nexin) proteins and Rab (Ras-associated binding protein) GTPases are key regulators of vesicle transport and endosomal sorting and are implicated in LDLR endocytosis, recycling, and subsequent cholesterol metabolism. This review aims to summarize the data on the roles of SNX17, Rab11, and Rab5 in LDLR recycling and endosomal dynamics, highlighting their potential as therapeutic targets for managing dyslipidemia and associated diseases.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e338-e354"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324370","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":"Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice.","authors":"Robert N Helsley, Mikala M Zelows, Victoria P Noffsinger, Garrett B Anspach, Nikitha Dharanipragada, Anna E Mead, Isidoro Cobo, Abigail Carter, Qinglin Wu, Irina Shalaurova, Kai Saito, Josh M Morganti, Scott M Gordon, Gregory A Graf","doi":"10.1161/ATVBAHA.125.322473","DOIUrl":"10.1161/ATVBAHA.125.322473","url":null,"abstract":"<p><strong>Background: </strong>Genome- and epigenome-wide association studies have associated variants and methylation status of CPT1a (carnitine palmitoyltransferase 1a) to reductions in VLDL (very low-density lipoprotein) cholesterol and triglyceride levels. The objective of this study was to determine the mechanisms by which CPT1a-dependent mitochondrial fatty acid oxidation influences hepatic and lipoprotein metabolism.</p><p><strong>Methods: </strong>Eight-week-old male and female <i>Cpt1a</i>-floxed mice (<i>Cpt1a</i>^fl/fl) and <i>Cpt1a</i>-floxed mice expressing the human apo B₁₀₀ transgene (<i>Cpt1a</i>^fl/fl/B100^Tg) were administered control adeno-associated virus or adeno-associated virus encoding Cre-recombinase under control of a liver-specific promoter (TBG-Cre [thyroxin-binding globulin]). Control and liver-specific knockout mice were placed on a low-fat control or western-type diet (42% kcal fat, 0.2% cholesterol) for 16 weeks. Livers were collected and used for histological and lipid analysis, while gene and protein expression were measured by bulk RNA-sequencing and immunoblotting, respectively. Lipoprotein composition in plasma was determined by size exclusion chromatography and nuclear magnetic resonance. Rates of VLDL-triglyceride secretion were quantified after lipase inhibition with poloxamer 407. Liquid and gas chromatography-mass spectrometry were used to measure bile acid species and fecal neutral sterols, respectively.</p><p><strong>Results: </strong>We report significant associations between the presence of <i>CPT1a</i> SNPs (single nucleotide polymorphisms) and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild-type and human apo B₁₀₀ (apoB)-transgenic mice with liver-specific deletion of <i>Cpt1a</i> (liver-specific knockout) display lower circulating apoB levels consistent with reduced LDL (low-density lipoprotein)-cholesterol and LDL particle number. Despite a reduction in steady-state plasma lipids, VLDL-triglyceride and VLDL cholesterol secretion rates are increased, suggesting accelerated clearance of apoB-LPs (apoB-containing lipoproteins) in liver-specific knockout mice. Mechanistic approaches show greater PPARα (peroxisome proliferator-activated receptor α) signaling which favors enhanced lipoprotein lipase-mediated metabolism of apoB-LPs, including increases in apo AIV and apo CII and reductions in apo CIII and Angptl3 (angiopoietin-like 3).</p><p><strong>Conclusions: </strong>These studies provide mechanistic insight linking genetic variants and methylation status of <i>CPT1a</i> to reductions in circulating apoB-LPs in humans.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1368-1388"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12286734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274117","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":"Change in Arterial Stiffness Is Associated With Change in Blood Glucose: Longitudinal Study in the Whitehall II Cohort.","authors":"Rachel E Climie, S Rehman, E J Brunner, P Boutouyrie, R M Bruno, J P Empana","doi":"10.1161/ATVBAHA.124.322001","DOIUrl":"10.1161/ATVBAHA.124.322001","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is associated with elevated large artery stiffening, but arterial stiffening may also precede the development of type 2 diabetes. Whether the change in arterial stiffness over time is associated with dysglycemia across the entire spectrum of blood glucose concentration is unknown. Therefore, the primary objective of this study was to quantify the association between the change in arterial stiffness (exposure) and glycemic concentration (outcome).</p><p><strong>Methods: </strong>Within the prospective WHS II (Whitehall II Study), arterial stiffness was first measured in the 2007/09 examination round (baseline for the current study) and again in 2012/13, using the noninvasive, gold-standard method of carotid to femoral pulse wave velocity (cfPWV). Change in cfPWV was determined as cfPWV in 2012/13-cfPWV-cfPWV in 2007/09. Fasting blood glucose concentrations were measured at baseline (2007/09) and follow-up in 2012/13 and 2015/16.</p><p><strong>Results: </strong>There were 2632 participants without prior type 2 diabetes and cfPWV measured at 2 timepoints with follow-up in 2012/13 and 2282 with follow-up in 2015/16. Greater change in cfPWV was associated with significantly higher fasting glucose concentration at follow-up in 2012/13 and 2015/16 independently of confounders including cfPWV and fasting glucose levels at baseline (<i>P</i><0.001 for both). Greater change in cfPWV was significantly and independently associated with a greater change in fasting glucose concentration over the same period (2007/09-2012/13) and beyond (2007/09-2015/16).</p><p><strong>Conclusions: </strong>Minimizing premature arterial stiffening over time could be a valuable strategy for the prevention of glucose dysregulation and overt type 2 diabetes.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1459-1467"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324366","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":"IL1β Secretion by Epididymal White Adipose Tissue Macrophages Regulates Myelopoiesis and Plaque Inflammation in Obese Mice and in Caloric Restriction.","authors":"Zhixing Li, Franziska Krautter, Maxwell La Forest, Edward A Fisher","doi":"10.1161/ATVBAHA.125.322789","DOIUrl":"10.1161/ATVBAHA.125.322789","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1468-1470"},"PeriodicalIF":7.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12286714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493819","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":"https://doi.org/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":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-24","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":"Chronic Pod-Mod E-Cigarette Aerosol Exposure Induces Aortic Dysfunction in Hypercholesterolemic Mice: Role of Oxidative Stress and Inflammation.","authors":"Yasmeen M Farra, Simone Sabnis, Jacqueline Matz, Hannah Wilker, Victoria A Williams, Oliver Trejo, Hannah Kim, Cristobal Rivera, John Vlahos, Bhama Ramkhelawon, Jessica M Oakes, Chiara Bellini","doi":"10.1161/ATVBAHA.125.320908","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.320908","url":null,"abstract":"<p><strong>Background: </strong>Electronic cigarettes (e-cigarettes) are the most used tobacco product among youth, and adults who smoke combustible cigarettes favor e-cigarettes over approved cessation aids. Despite the lower perceived harm of vaping compared with smoking, acute inhalation of e-cigarette aerosol elicits cardiovascular responses that may lead to persistent damage when repeated over time.</p><p><strong>Methods: </strong>We exposed female hypercholesterolemic mice to either pod-mod e-cigarette aerosol or filtered air daily for 24 weeks. We assessed the long-term effects of vaping on aortic stiffness and vasoreactivity while investigating the underlying cellular and molecular mechanisms of injury.</p><p><strong>Results: </strong>Chronic inhalation of e-cigarette aerosol triggered the accumulation of inflammatory signals systemically and within aortic tissues, as well as T-lymphocyte accrual in the aortic wall. Limited eNOS (endothelial nitric oxide synthase) expression and enhanced superoxide radical production curbed NO bioavailability in the aorta of mice exposed to e-cigarette aerosol despite iNOS (inducible nitric oxide synthase) induction, impairing the endothelium-dependent vasodilation that regulates blood flow distribution. Inhalation of e-cigarette aerosol thickened and stiffened aortic tissues via collagen deposition and remodeling, hindering the storage of elastic energy and limiting the cyclic distensibility that enables the aorta to function as a pressure reservoir. These effects combined contributed to raising systolic and pulse pressure above control levels.</p><p><strong>Conclusions: </strong>Chronic inhalation of aerosol from pod-mod e-cigarettes promotes oxidative stress, inflammation, and fibrosis within aortic tissues, significantly impairing passive and vasoactive aortic functions. This evidence provides new insights into the biological processes that increase the risk of adverse cardiovascular events as a result of pod-mod e-cigarette vaping.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697539","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":"Identification of Myeloid Protein Kinase C Epsilon as a Novel Atheroprotective Gene.","authors":"Alexis T Wells, Ramon Bossardi Ramos, Michelle M Shen, Redwan H Binrouf, Anna E Swinegar, Michelle R Lennartz","doi":"10.1161/ATVBAHA.125.323005","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.323005","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Atherosclerosis is a chronic inflammatory disease driven by macrophages. PKCɛ (protein kinase C epsilon) is a serine/threonine kinase involved in diverse cellular processes including migration, growth, differentiation, and survival. PKCɛ acts in a context-dependent manner within the heart; however, its role in atherosclerosis is unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Bone marrow-derived macrophages from global PKCɛ knockout mice were tested for lipid retention and cytokine secretion. Public gene set analysis assessed raw counts of PRKCE in human atheromas to determine translational relevance. A LysM Cre PKCɛ&lt;sup&gt;fl/fl&lt;/sup&gt; (myeloid-selective PKCɛ knockout [mɛKO]) mouse was developed to study the impact of myeloid PKCɛ on atherosclerosis. After confirming myeloid-selective PKCɛ deletion, human-like hypercholesterolemia was induced, and multiple metrics of atherosclerosis were compared in wild-type (WT) and mɛKO plaques. RNA sequencing was used to provide unbiased insight into possible mechanisms by which PKCɛ regulates atherosclerosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Public gene set analysis of human atherosclerotic plaque tissue revealed that PKCɛ expression is inversely correlated with plaque vulnerability. Similarly, peritoneal macrophages from WT hypercholesterolemic mice have significantly lower PKCɛ expression, providing a translational rationale for the generation of the mɛKO mouse. Quantitative polymerase chain reaction revealed no differences between genotypes in the expression of genes related to atherosclerosis, at either steady state or on lipid loading, suggesting that loss of PKCɛ does not fundamentally change the basal state and that differences seen are a result of a more complex pathway. Comparing descending aorta and aortic root plaques from WT and mɛKO hypercholesterolemic mice revealed that mɛKO plaques are larger, have larger foam cells and regions of necrosis, and thinner collagen caps. On lipid loading in vitro and in vivo, mɛKO macrophages retained significantly more cholesterol and lipid droplets than WT; Gene Ontology suggests higher expression of genes related to endocytosis in mɛKO macrophages compared with WT.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;PKCɛ expression is decreased in vulnerable human plaques and decreases in mouse macrophages on lipid loading. mɛKO plaques are larger and exhibit markers of vulnerability. With no differences in SR (scavenger receptor) expression, the impact of PKCɛ deletion is more subtle than simple SR dysregulation. RNA sequencing implicates higher expression of genes involved in endocytosis, and mɛKO macrophages have significantly more lipid-containing endosomes. The data define the atherophenotype of mɛKO mice and demonstrate that PKCɛ restricts lipid uptake into macrophages by a mechanism independent of SR expression. Taken together, these studies identify PKCɛ as a novel atheroprotective gene, laying the foundation for mechanistic studies on the endocyt","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697541","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":"Circulating Protein Mediators Linking Genetically Predicted Smoking to Abdominal Aortic Aneurysm: A Genomic-Proteomic Analysis.","authors":"Shuai Yuan, Samuel Khodursky, Jiawei Geng, Pranav Sharma, Joshua M Spin, Philip Tsao, Michael G Levin, Scott M Damrauer","doi":"10.1161/ATVBAHA.125.323057","DOIUrl":"10.1161/ATVBAHA.125.323057","url":null,"abstract":"<p><strong>Background: </strong>Smoking is a well-established risk factor for abdominal aortic aneurysm (AAA). However, the molecular pathways underlying this relationship remain poorly understood. This study aimed to identify circulating protein mediators that may explain the association between smoking and AAA.</p><p><strong>Methods: </strong>We conducted a network Mendelian randomization study using summary-level data from the largest available genome-wide association studies. Our primary smoking exposure was the lifetime smoking index, with smoking initiation and cigarettes per day included as supplementary traits. The AAA data set comprised 39 221 cases and 1 086 107 controls. Protein data were sourced from 2 large cohorts: UKB-PPP (the UK Biobank Pharma Proteomics Project), where proteins were measured using the Olink platform in 54 219 individuals, and deCODE, where proteins were measured using the SomaScan platform in 35 559 individuals. Two-sample Mendelian randomization was used to estimate the association between smoking and AAA (β_total) and between smoking and circulating protein levels (β₁). Summary data-based Mendelian randomization was then used to assess the association between smoking-related proteins and AAA risk (β₂). Mediation pathways were identified based on the directionality of effect estimates, and the corresponding mediation effects were quantified.</p><p><strong>Results: </strong>Genetically proxied smoking traits were consistently associated with an increased risk of AAA. The lifetime smoking index was associated with the levels of 543 out of 5764 unique circulating proteins, with 470 of these associations replicated in supplementary analyses using additional smoking traits and protein sources. Among the smoking-related proteins, genetically proxied levels of 22 were associated with AAA risk. Eight mediation pathways were identified, with ADAMTS15 (a disintegrin and metalloproteinase with thrombospondin motifs 15), IL1RN (interleukin-1 receptor antagonist protein), MMP12 (matrix metalloproteinases 12), PGF (placental growth factor), PCSK9 (proprotein convertase subtilisin/kexin type 9), and UXS1 (UDP-glucuronic acid decarboxylase 1) representing key mediators.</p><p><strong>Conclusions: </strong>This study identified numerous circulating proteins that are potentially causally linked to smoking, and 8 of these proteins were found to mediate the association between smoking and AAA risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648406","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":"Bone Marrow Farnesoid X Receptor Deficiency Does Not Impact Atherosclerosis Susceptibility in Male Low-Density Lipoprotein Receptor Knockout Mice.","authors":"Menno Hoekstra, Ruud Out, Zhaosha Li, Reeni B Hildebrand, Theo J C Van Berkel, Miranda Van Eck","doi":"10.1161/ATVBAHA.125.322834","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322834","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599253","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 Benguria, Ana Dopazo, Fátima Sanchez-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":"https://doi.org/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":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}