Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"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 I B Wilker, Victoria A Williams, Oliver Trejo, Hannah Kim, Cristobal F Rivera, John Vlahos, Bhama Ramkhelawon, Jessica M Oakes, Chiara Bellini","doi":"10.1161/ATVBAHA.125.320908","DOIUrl":"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":"1574-1592"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370285/pdf/","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":"OA","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":"10.1161/ATVBAHA.125.323005","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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^fl/fl (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 between wild-type (WT) and mɛKO plaques. RNA sequencing was used to provide unbiased insight into possible mechanisms by which PKCɛ regulates atherosclerosis.</p><p><strong>Results: </strong>Public gene set analysis of human atherosclerotic plaque tissue revealed that PRKCE 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 upon 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. Upon 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.</p><p><strong>Conclusions: </strong>PRKCE expression is decreased in vulnerable human plaques and PKCɛ decreases in mouse macrophages upon 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 stud","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e392-e411"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12364379/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: AIP1 Mediates Vascular Endothelial Cell Growth Factor Receptor-3-Dependent Angiogenic and Lymphangiogenic Responses.","authors":"Huanjiao Jenny Zhou, Xiaodong Chen, Qunhua Huang, Renjing Liu, Haifeng Zhang, Yingdi Wang, Yu Jin, Xiaoling Liang, Lin Lu, Zhe Xu, Wang Min","doi":"10.1161/ATV.0000000000000188","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000188","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 9","pages":"e468"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940452","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":"Binding of Hypoxia-Induced Mitogenic Factor/RELM-β to Bone Morphogenetic Protein Receptor 2 Complex Promotes Pulmonary Hypertension.","authors":"Ting Zhang, Liping Zhu, Bingxun Liu, Jie Liu, Xianqin Zeng, Wenbo Yang, Matthieu Ruiz, Jocelyn Dupuis, Rui Xiao, Qinghua Hu","doi":"10.1161/ATVBAHA.125.322652","DOIUrl":"10.1161/ATVBAHA.125.322652","url":null,"abstract":"<p><strong>Background: </strong>HIMF (hypoxia-induced mitogenic factor) induces pulmonary hypertension; however, the molecular nature of its extracellular membrane receptor(s) remains unknown.</p><p><strong>Methods: </strong>A combination of cross-immunoprecipitation and immunoblotting, yeast 2-hybrid assays, and proteomics analysis was performed to screen and identify the candidate receptors. The interaction of HIMF with these candidate(s) was further evaluated using overexpression, silencing, point mutation, and blocking peptide strategies in chronic hypoxia and sugen/hypoxia pulmonary hypertension rat models to decipher the underlying pathophysiologic mechanisms.</p><p><strong>Results: </strong>Cross-immunoprecipitation and immunoblotting identified HIMF interaction with the BMPR2 (bone morphogenetic protein receptor 2) complex. Yeast 2-hybrid revealed HIMF binding to the DTLPF motif (Asp-Thr-leucine-Pro-Phe [aspartic acid-threonine-leucine-proline-phenylalanine]) at the 54 to 58 amino acids (aa) in the extracellular domain of the BMPR1A (bone morphogenetic protein receptor 1A), one partner of the BMPR2 heterodimeric complex, but not BMPR2 itself. HIMF and human counterpart RELM (resistin-like molecule)-β binding to BMPR1A disrupted the BMPR1A/BMPR2 complex and decreased BMPR2 activity as revealed by reduced downstream events including ≈43% to 56% decline in Smad1/5/9 (Sma- and Mad-related protein 1/5/9) phosphorylation and ≈41% to 60% decrease in Id-1 (inhibitor of DNA binding 1) expression. This dynamic induced pulmonary artery smooth muscle cell proliferation and pulmonary vascular remodeling leading to pulmonary hypertension. A mutated motif in rats or a blocking peptide targeting this motif restrained HIMF binding with BMPR1A, rescued BMPR2 activity by ≈25% increase in Smad/1/5/9 phosphorylation and ≈39% elevation in Id-1 expression, and attenuated chronic hypoxia or sugen/hypoxia-induced pulmonary hypertension.</p><p><strong>Conclusions: </strong>HIMF induced pulmonary hypertension by direct binding to BMPR1A ectodomain, subsequently disrupting its binding to BMPR2 and BMPR2 activity. This HIMF signaling pathway represents a potential therapeutic target by selectively interfering with BMPR1A binding.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1593-1615"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793345","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":"Circular RNAs Complement Cardiovascular Messaging Machinery.","authors":"Muntadher Al Zaidi, Georg Nickenig","doi":"10.1161/ATVBAHA.125.323371","DOIUrl":"10.1161/ATVBAHA.125.323371","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1562-1564"},"PeriodicalIF":7.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793347","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":"SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity.","authors":"Payel Chatterjee, Raja Chakraborty, Ashley J Sizer, Brendan J O'Brien, Peng Xu, Jonathan M Hwa, Yi Xie, Qin Yan, John Hwa, Kathleen A Martin","doi":"10.1161/ATVBAHA.124.322179","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322179","url":null,"abstract":"<p><strong>Background: </strong>Reversible DNA methylation contributes to vascular smooth muscle cell (VSMC) phenotypic plasticity. This plasticity contributes to vascular growth and remodeling but also underlies pathologies, including intimal hyperplasia. We investigated the role of SUV39H1 (suppressor of variegation 3-9 homolog 1), a histone methyltransferase that generates trimethylation at histone H3 lysine 9 (H3K9me3), a repressive heterochromatin-associated epigenetic mark, in VSMC plasticity.</p><p><strong>Methods: </strong>We applied knockdown, quantitative polymerase chain reaction, Western blotting, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing, and RNA-sequencing in human coronary artery smooth muscle cells and murine carotid ligation to assess SUV39H1 functions in VSMC plasticity.</p><p><strong>Results: </strong>In normal mouse carotid artery, SUV39H1 and H3K9me3 were markedly increased, while the cognate H3K9me3 demethylase KDM4A rapidly decreased with carotid ligation and neointimal hyperplasia. In human coronary artery smooth muscle cells, SUV39H1 knockdown induced contractile genes, morphology, and contractility but inhibited migration and proliferation. We found that SUV39H1 was required for PDGF (platelet-derived growth factor) induction of KLF4, regulating miR143, KLF4 mRNA stability, and promoter accessibility. PDGF-induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification at contractile gene promoters. SUV39H1 knockdown increased KDM4A expression and binding to contractile promoters, suggesting an opposing regulatory relationship between the H3K9me3 writer and eraser in VSMCs. Chromatin immunoprecipitation assays with SUV39H1 knockdown revealed that SUV39H1 modifies H3K9me3 but also promotes a repressive state (increased 5mC and reduced H3K27Ac) at contractile gene promoters. Conversely, SUV39H1 induced an active state at the KLF4 promoter, reducing DNMT1 (DNA methyltransferases 1) recruitment and 5mC levels. Assay for transposase-accessible chromatin using sequencing revealed that SUV39H1 oppositely modifies chromatin accessibility at phenotype-specific human coronary artery smooth muscle cell promoters genome-wide. Consistently, transcriptomic profiling showed that SUV39H1 and TET2 oppositely influence SMC gene expression.</p><p><strong>Conclusions: </strong>We identify SUV39H1 as a potent PDGF-induced epigenetic regulator that promotes KLF4 expression and VSMC dedifferentiation. SUV39H1 regulates dynamic trimethylation at histone H3 lysine 9 in phenotypic switching, regulating mark deposition and the KDM4A demethylase. We report that SUV39H1 coordinately regulates DNA and histone methylation and histone acetylation. This altered chromatin accessibility by a heterochromatin-associated enzyme represents a new mechanism underlying VSMC plasticity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940378","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":"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}

{"title":"Single-Cell Multimodal Profiling Reveals a Novel CD26⁺ 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⁺ 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⁺ 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}

{"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)^<i>-/-</i>, <i>Aep</i>^<i>-/-</i><i>Apoe</i>^<i>-/-</i>, 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>^<i>-/-</i> 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}

{"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}