Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Estimated Small, Dense LDL Cholesterol and Atherosclerotic Cardiovascular Risk in the UK Biobank.","authors":"Rafael Zubiran, Maureen Sampson, Anna Wolska, Alan T Remaley","doi":"10.1161/ATVBAHA.125.323157","DOIUrl":"10.1161/ATVBAHA.125.323157","url":null,"abstract":"<p><strong>Background: </strong>A key step in primary prevention is the assessment of atherosclerotic cardiovascular disease (ASCVD) risk. Risk enhancer tests are additional tools used to further improve ASCVD risk assessment over conventional risk markers. Our objective was to determine whether estimated small, dense low-density lipoprotein cholesterol (E-sdLDL-C) can improve risk assessment and serve as a new risk enhancer test.</p><p><strong>Methods: </strong>We used a prospective cohort analysis of participants in the UK Biobank study with a median (interquartile range) follow-up of 10 (6.7-12.3) years. We included 271 760 individuals who were not on lipid-lowering medication at baseline and did not have incident ASCVD. The primary study outcome was the incidence of all-cause ASCVD.</p><p><strong>Results: </strong>E-sdLDL-C was strongly associated with ASCVD events with a hazard ratio (HR) of 1.23 (95% CI, 1.22-1.24). After multivariable adjustment for age, sex, systolic blood pressure, hypertension, type 2 diabetes, and blood pressure medications, E-sdLDL-C and ApoB (apolipoprotein B) remained the most significant lipid risk factors (HR, 1.18 [95% CI, 1.16-1.19] and 1.17 [95% CI, 1.16-1.18] per SD, respectively). After further adjustment for ApoB, the association between low-density lipoprotein cholesterol (LDL-C) with all-cause ASCVD was completely reversed with an HR of 0.84 (95% CI, 0.81-0.86), but E-sdLDL-C continued to have a significant positive association with an HR of 1.11 (95% CI, 1.08-1.13). When E-sdLDL-C was discordantly higher than either LDL-C or ApoB, the risk for ASCVD was higher (LDL-C, 31% higher; ApoB, 17% higher). When elevated E-sdLDL-C is coupled with other risk enhancer tests, there is a greater risk for developing ASCVD.</p><p><strong>Conclusions: </strong>In a UK Biobank cohort for primary prevention, the risk of all-cause ASCVD was better captured by E-sdLDL-C than LDL-C. It was also more predictive than LDL-C and ApoB when discordant with these 2 measures. E-sdLDL-C, which can be freely and automatically calculated from a standard lipid panel, can potentially improve ASCVD risk assessment without additional laboratory testing.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e512-e522"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844305","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":"EcoHIV Infection Promotes Atherosclerosis Progression in LDLR-Deficient Mice.","authors":"Ivan Pinos, Amparo Blanco, Jennifer Kelschenbach, Mike Veenstra, Eva Hu, Hongxia He, Joan W Berman, David J Volsky, Jaume Amengual","doi":"10.1161/ATVBAHA.125.323004","DOIUrl":"10.1161/ATVBAHA.125.323004","url":null,"abstract":"<p><strong>Background: </strong>People with HIV are at higher risk of atherosclerotic cardiovascular disease than uninfected individuals; however, the molecular mechanisms behind this association remain elusive due to the lack of suitable animal models.</p><p><strong>Methods: </strong>To study the impact of HIV on atherosclerotic cardiovascular disease, we infected the atheroprone <i>Ldlr</i>^<i>-/-</i> mice with the chimeric virus EcoHIV.</p><p><strong>Results: </strong>In comparison to uninfected controls, EcoHIV infection increased the ratio of circulating inflammatory monocytes, monocyte recruitment, and CD68⁺ content in the atherosclerotic lesion. These changes occurred independently of alterations in plasma lipid profile or lesion size between groups. Lesions of EcoHIV-infected mice displayed greater vulnerability to rupture, as determined by increased necrotic core area and CD38⁺ content, and reduced presence of collagen compared with uninfected mice. Last, we report the presence of active viral replication of EcoHIV in the atherosclerotic lesion.</p><p><strong>Conclusions: </strong>Our data suggest that EcoHIV infection in <i>Ldlr</i>^<i>-/-</i> mice resembles the pathogenesis of atherosclerotic cardiovascular disease in people with HIV. Our findings have therapeutic implications for people with HIV, a vulnerable population with an elevated risk of cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e470-e482"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991509","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":"Poor Collateralization in T2DM: Role of SLC4A10+ MAIT Cells.","authors":"Shuai Chen, Ke Huang, Ting Zhang, Zhi-Ming Wu, Fei-Fei Li, Yipaerguli Maimaiti, Xue-Lian Wang, Jing-Meng Liu, Xin-Rui Wu, Qiu-Jing Chen, Ying Shen, Xiao-Qun Wang, Ruo-Sen Yuan, Wen-Jia Li, Lin Lu, Yang Dai, Feng-Hua Ding","doi":"10.1161/ATVBAHA.125.322718","DOIUrl":"10.1161/ATVBAHA.125.322718","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes is strongly associated with impaired collateralization, which increases the risk of cardiovascular complications, such as myocardial infarction and heart failure. This study explored the immune cell dynamics in patients with type 2 diabetes with chronic total occlusion and their impact on collateralization.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells were extracted from patients with type 2 diabetes with chronic total occlusion, exhibiting either good or poor collateralization. Single-cell RNA sequencing was conducted to profile the quantitative and transcriptomic dynamics of immune cells in these 2 groups. Moreover, coculture experiments were executed, and ischemic models of the hindlimb and myocardium were induced in diabetic mice to corroborate the single-cell RNA sequencing findings. Additional validation was attained by conducting an analysis on a separate cohort of patients.</p><p><strong>Results: </strong>Single-cell RNA sequencing of peripheral blood mononuclear cells identified elevated levels of mucosal-associated invariant T (MAIT) cells in patients with poor collateralization. In diabetic mice, inhibition of MAIT cell activation significantly improved angiogenesis under ischemic conditions. In vitro, MAIT cell-derived CCL3L1 (C-C motif chemokine ligand 3-like 1) drove macrophage polarization toward a proinflammatory phenotype through CCR5 (C-C chemokine receptor type 5) interaction. Furthermore, an independent patient cohort confirmed that elevated MAIT cell levels represent an independent risk factor for poor collateralization.</p><p><strong>Conclusions: </strong>These findings highlight the critical role of MAIT cells in regulating collateralization in type 2 diabetes chronic total occlusion patients and propose circulating MAIT cell levels as a potential biomarker for predicting and intervening in poor collateralization.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1893-1911"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844281","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":"Efficient Fine-Tuning of Endothelial Gene Expression by a Single Tyrosine (Y⁶⁸⁵) to Phenylalanine Point Mutation in the VE-Cadherin Gene.","authors":"Olivia Garnier, Florian Jeanneret, Aude Durand, Arnold Fertin, Sarah Berndt, Gilles Carpentier, Christophe Battail, Donald K Martin, Isabelle Vilgrain","doi":"10.1161/ATVBAHA.125.323129","DOIUrl":"10.1161/ATVBAHA.125.323129","url":null,"abstract":"<p><strong>Background: </strong>VE (vascular endothelial)-cadherin is an endothelial cell-surface receptor that lacks intrinsic tyrosine kinase activity but can be tyrosine phosphorylated in cancer and inflammation. Previous studies have uncovered the molecular underpinnings of phosphorylation events; however, there is a need for a comprehensive analysis of the transcriptome of endothelial cells.</p><p><strong>Methods: </strong>Using a tyrosine-to-phenylalanine (Y->F) transgenic mouse (KI), we provide the first experimental evidence that tyrosine-to phenylalanine at the site 685 (Y⁶⁸⁵F)-VE-cadherin induces a specific transcriptional program in vivo in lung tissue.</p><p><strong>Results: </strong>RNA-sequencing analysis revealed a total of 884 differentially expressed genes (766 downregulated and 118 upregulated in endothelial cells from KI) involved in cell-cell adhesion, vascular development, and angiogenesis. The heatmap of the top 30 differentially expressed genes clearly shows 22 downregulated genes (including cell signaling enzymes, anion transport, and lipid metabolism) and 8 upregulated genes that confer significantly reduced migration, proliferation, and outgrowth capabilities to endothelial cells from KI. A central pathway in signal transduction revealed a notable increase in phosphorylation of site tyrosine 731 (Y⁷³¹) in Y⁶⁸⁵F-VE-cadherin in KI (<i>P</i>=0.041). This further compromised the binding of β-catenin, which was preferentially located in the nuclear fraction in KI (<i>P</i>=0.034) with increased transcriptional activity. One of the genes of particular interest was <i>s1pr1</i> (sphingosine-1-phosphate receptor 1), which had the highest mean expression level in KI. We identified the lung endothelial-specific transcription factor FOXF1 (forkhead box protein F1) that binds to the <i>s1pr1</i> promoter with a significantly higher intensity in KI (7-fold; <i>P</i>=0.023), as shown by chromatin immunoprecipitation assay. Consequently, increased <i>s1pr1</i> expression was confirmed by reverse transcription polymerase chain reaction and Western blotting. Importantly, quantitative analysis of the pulmonary vasculature of KI revealed a significant decrease in the number of capillaries (<i>P</i>=0.036), with less fibrosis and no edema.</p><p><strong>Conclusions: </strong>Overall, our results indicate a novel regulatory mechanism for transcriptional signatures in lung tissue, involving the critical site Y⁶⁸⁵ of VE-cadherin. This finding offers future insights for precision medicine applications.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1852-1871"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844304","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":"Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling.","authors":"Yannic Becker, Sergey Tkachuk, Anne Jörns, Nelli Shushakova, Song Rong, Ahmad Alwakaa, Jan Hegermann, Heiko Schenk, Yulia Kiyan, Hermann Haller","doi":"10.1161/ATVBAHA.125.323060","DOIUrl":"10.1161/ATVBAHA.125.323060","url":null,"abstract":"<p><strong>Background: </strong>Vessel-lining endothelial cells (ECs) rely on heparan sulfate (HS) proteoglycans to regulate vascular permeability and to maintain vascular homeostasis. Hpa2 (heparanase 2) is a little-known, nonenzymatic, HS-binding protein. We hypothesized major functions and thus characterized the role of endogenous Hpa2 in the vertebrate vascular system.</p><p><strong>Methods: </strong>We use zebrafish larvae as our primary animal model. Hpa2 loss-of-function (LOF) was induced by CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) and morpholino antisense strategies. We assessed vascular permeability, blood vessel architecture, and EC morphology using transgenic zebrafish and transmission electron microscopy. rHpa2 (recombinant heparanase 2) was generated to study the functionality of Hpa2 in endothelial tissue cultures, zebrafish, and mice.</p><p><strong>Results: </strong>We detected Hpa2 expression in hepatic tissue and localized Hpa2 protein in the vasculature of zebrafish and mammals. Hpa2 LOF increased zebrafish vascular permeability and altered EC and extracellular matrix morphology. rHpa2 rescued the Hpa2 LOF phenotype. Hpa2 LOF reduced HS levels and caused EC gene expression changes involved in signal transduction. rHpa2 competed with growth factors FGF2 (fibroblast growth factor-2) and VEGFA₁₆₅ (vascular endothelial growth factor A₁₆₅) for binding on the EC surface and consequently reduced the signal response these factors elicit. rHpa2 prevented VEGFA₁₆₅-induced vascular permeability in murine ex vivo kidneys. Pharmacological inhibition of FGF2/VEGFR (VEGF receptor) signaling alleviated the Hpa2 LOF phenotype in zebrafish.</p><p><strong>Conclusions: </strong>We suggest that Hpa2 is a circulating molecule that maintains vascular integrity by regulating vascular HS-dependent growth factor signaling. Our model outlines Hpa2-related vascular function and could indicate therapeutic utilities.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1835-1851"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940357","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":"Trimethylamine-<i>N</i>-Oxide Affects Cell Type-Specific Pathways and Networks in Mouse Aorta to Promote Atherosclerotic Plaque Vulnerability.","authors":"Jenny Cheng, Michael Cheng, Satyesh Sinha, Ingrid Cely, Sasha Gladkikh, Maggie T Han, Guanglin Zhang, Zhiqiang Zhou, Rubani Chugh, In Sook Ahn, Graciel Diamante, Yu-Chen Wang, Zeneng Wang, Brian J Bennett, Hua Cai, Hooman Allayee, Stanley L Hazen, Aldons J Lusis, Diana M Shih, Xia Yang","doi":"10.1161/ATVBAHA.125.323047","DOIUrl":"10.1161/ATVBAHA.125.323047","url":null,"abstract":"<p><strong>Background: </strong>Trimethylamine-<i>N</i>-oxide (TMAO) has been significantly linked to atherosclerosis via several mechanisms, but its direct effect on the atherosclerosis-prone vasculature remains unclear. The objective of this study was to characterize the cell type-dependent and independent effects of TMAO on key vascular cell types involved in atherosclerosis progression in vivo.</p><p><strong>Methods: </strong>We performed single-cell RNA-sequencing on aortic athero-prone regions of female <i>Ldlr</i>^<i>-/-</i> mice fed normal laboratory, high-cholesterol, or high-cholesterol+TMAO diets for 3 months to identify which aortic cell types, differentially expressed genes, and biological pathways are affected by TMAO. We also modeled cell-cell communications and intracellular gene regulatory networks to identify gene networks perturbed by TMAO feeding. Key genes and pathways were validated using human vascular smooth muscle cells (vSMCs) exposed to TMAO. Changes in fibrous cap thickness, macrophage content, and collagen deposition in response to TMAO were measured with immunostaining and histology and quantified.</p><p><strong>Results: </strong>Our single-cell RNA-sequencing analysis revealed that TMAO supplementation upregulated apoptotic gene signatures and downregulated extracellular matrix (ECM) organization and collagen formation genes in a subset of atherosclerosis-specific modulated vSMCs. We also identified degradation of the ECM as a top pathway for vSMC-derived macrophage differentially expressed genes in response to TMAO. Network analyses supported that macrophage-vSMC communication mediates ECM remodeling. Using human smooth muscle cells exposed to TMAO in vitro, we confirmed the direct effect of TMAO on regulating collagen and apoptotic genes. In agreement with the changes in these pathways that affect plaque stability, we observed a significant decrease in fibrous cap thickness and collagen deposition in mice supplemented with TMAO.</p><p><strong>Conclusions: </strong>Our results reveal the effects of TMAO on vSMCs to promote apoptosis and decrease ECM formation and on macrophage-mediated ECM degradation to, in concert enhance atherosclerotic plaque instability.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1784-1798"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844283","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":"TGF-β1 Promotes Angiogenesis via Endothelial-to-Mesenchymal Transition in Infantile Hemangioma.","authors":"Xue Gong, Tong Qiu, Jiangyuan Zhou, Kaiying Yang, Shanshan Xiang, Zixin Zhang, Yuru Lan, Xuepeng Zhang, Zilong Zhou, Congxia Yang, Yujia Zhang, Siyuan Chen, Yi Ji","doi":"10.1161/ATVBAHA.125.322793","DOIUrl":"10.1161/ATVBAHA.125.322793","url":null,"abstract":"<p><strong>Background: </strong>Infantile hemangioma (IH) is the most common benign tumor in infancy and severely affects aesthetics and function. Hemangioma-derived endothelial cells (HemECs) are the main cellular component of IH and contribute to angiogenesis in IH. TGF-β1 (transforming growth factor β1) can induce endothelial-to-mesenchymal transition (EndoMT). Few studies have investigated the role and mechanism of TGF-β1-mediated EndoMT in IH angiogenesis.</p><p><strong>Methods: </strong>The expression of EndoMT markers in IH samples was evaluated via multiplexed immunofluorescence assay. Lentiviruses and small interfering RNA were used to regulate gene expression. Targeted lipidomic analysis was subsequently conducted. Protein interactions between TGF-β1 and potential effectors were examined. Biological changes in function were measured by migration, invasion, and tube formation in vitro and vessel formation in vivo. Autophagy-related structures were detected via transmission electron microscopy. BALB/C-nude mice were used for the hemangioma model.</p><p><strong>Results: </strong>In this study, the active participation of EndoMT in proliferating IH was verified. TGF-β1^OE (TGF-β1 overexpression) induced EndoMT and promoted the migration, invasion, and angiogenic abilities of HemECs. In addition, TGF-β1^OE decreased the protein expression of CPT1A (carnitine palmitoyltransferase 1A). TGF-β1 treatment decreased the levels of L-palmitoylcarnitine (a downstream metabolite of CPT1A) in HemECs. Supplementation with L-palmitoylcarnitine partly reversed the functional changes caused by CPT1A^KD (CPT1A knockdown). Furthermore, the effect of TGF-β1^OE+overexpression model of CPT1A was similar to that of CPT1A^KD+L-palmitoylcarnitine in regulating the functional behaviors of HemECs. R(+) propranolol inhibited HemECs EndoMT and vessel formation in vivo.</p><p><strong>Conclusions: </strong>TGF-β1-mediated EndoMT promotes angiogenesis in IH. Targeting TGF-β1 could be a promising therapeutic strategy for inhibiting IH progression.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1912-1927"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940365","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":"Oxidized Phospholipids on ApoB-100, Platelet Activation and Reactivity, and Long-Term Cardiovascular Outcomes.","authors":"Sotirios Tsimikas, Alexander Kille, Klaus Kaier, Thomas Nührenberg, Kilian Franke, Christian M Valina, Xiaohong Yang, Gregor Leibundgut, Franz-Josef Neumann, Dirk Westermann, Willibald Hochholzer","doi":"10.1161/ATVBAHA.125.322347","DOIUrl":"10.1161/ATVBAHA.125.322347","url":null,"abstract":"<p><strong>Background: </strong>OxPL-apoB (oxidized phospholipids [OxPL] on apoB-100), which include OxPL present on Lp(a) (lipoprotein[a]), are associated with higher cardiovascular risk. Experimental studies suggest that OxPL may influence platelet function.</p><p><strong>Methods: </strong>This observational study assessed the association of OxPL-apoB with intrinsic and on‑clopidogrel platelet reactivity and long-term cardiovascular events in patients undergoing coronary angiography with or without percutaneous coronary intervention in 2040 patients in the EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate). The association of OxPL-apoB to expression of CD62P, CD41, or PAC-1 levels and intrinsic and on-clopidogrel platelet reactivity to collagen and ADP was determined. The relationship of OxPL-apoB and Lp(a) to myocardial infarction-free survival and all-cause mortality at a median of 7 years was assessed using Cox regression models.</p><p><strong>Results: </strong>Elevated levels of OxPL-apoB were associated with the severity of coronary obstruction, and higher prevalence of prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass graft surgery. No significant associations were present between OxPL-apoB and intrinsic or on-clopidogrel platelet reactivity or activation of platelet receptors. Analyzed individually in separate multivariable models, both OxPL-apoB (hazard ratio, 1.022 [95% CI, 1.005-1.040]; <i>P</i>=0.010) and Lp(a) (hazard ratio, 1.002 [95% CI, 1.000-1.005]; <i>P</i>=0.032) were associated with worse myocardial infarction-free survival. However, in a joint multivariable model analyzed together, neither OxPL-apoB nor Lp(a) was significant. The optimal cut point for myocardial infarction-free survival for OxPL-apoB was 8 nmol/L (hazard ratio, 1.391 [95% CI, 1.086-1.780]; <i>P</i>=0.009) and for Lp(a) 30 mg/dL (hazard ratio, 1.261 [95% CI, 1.012-1.570]; <i>P</i>=0.038).</p><p><strong>Conclusions: </strong>In patients undergoing coronary angiography with or without percutaneous coronary intervention, OxPL-apoB was not associated with intrinsic and on-clopidogrel platelet reactivity mediated by collagen or ADP. The association of OxPL-apoB and Lp(a) suggests that the accumulation of OxPL on Lp(a) may be a key determinant of long-term cardiovascular outcomes.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT00457236.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1935-1944"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844306","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":"GRK2 Orchestrates VSMC Phenotypic Modulation via DNMT1-Mediated DNA Methylation Reprogramming.","authors":"Chao-Hua Kong, Yue Sun, Li-da Wu, Wen-Ying Zhou, Dong-Chen Wang, Zi-Hao Jiang, Xiao-Min Jiang, Peng Ye, Yue Gu, Ai-Qun Chen, Jin-Que Luo, Yue-Lin Chao, Shao-Liang Chen","doi":"10.1161/ATVBAHA.125.322645","DOIUrl":"10.1161/ATVBAHA.125.322645","url":null,"abstract":"<p><strong>Background: </strong>Vascular smooth muscle cell (VSMC) phenotypic modulation is responsible for the pathogenesis of hyper-muscularized arterial diseases. Recent studies have highlighted the critical role of epigenetic regulation in VSMC fate. However, the mechanisms underlying the precise regulation of the epigenetic machinery in VSMC remain unclear.</p><p><strong>Methods: </strong>Using mouse aortic smooth muscle cells, carotid artery injury mouse model, and human atherosclerosis data sets, we identified GRK2 (G-protein-coupled receptor kinase 2) as a novel epigenetic regulator governing VSMC fate.</p><p><strong>Results: </strong>GRK2 expression was found to be elevated in dedifferentiated VSMCs. Pharmacological or genetic silencing of GRK2 inhibited VSMC phenotypic switching. Mechanistic investigations demonstrated that GRK2 modulated VSMC phenotype via DNMT1 (DNA methyltransferase 1)-mediated DNA methylation. GRK2 phosphorylated DNMT1, stabilizing it by modulating its ubiquitination. Hypermethylated VSMC exhibited reduced expression of contractile-associated proteins. Inhibition of DNMT1 abolished the effects of GRK2 overexpression on VSMC phenotype, indicating a DNMT1-mediated mechanism.</p><p><strong>Conclusions: </strong>Our findings revealed that the GRK2-DNMT1 signaling axis is a critical regulator in VSMC phenotypic switching and present a potential therapeutic target for vascular remodeling.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1818-1834"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940293","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":"Sexual Dimorphism of Plasma and Tissue Proteomes in Human Calcific Aortic Valve Stenosis Pathogenesis-Brief Report.","authors":"Cassandra L Clift, Mark C Blaser, Francesca Bartoli-Leonard, Florian Schlotter, Hideyuki Higashi, Shiori Kuraoka, Taku Kasai, Mandy E Turner, Tan Pham, Katelyn A Perez, Simon C Robson, Simon C Body, Jochen D Muehlschlegel, Masanori Aikawa, Sasha A Singh, Elena Aikawa","doi":"10.1161/ATVBAHA.125.322560","DOIUrl":"10.1161/ATVBAHA.125.322560","url":null,"abstract":"<p><strong>Background: </strong>Calcific aortic valve stenosis is a global clinical burden, impacting around 2% of the population over 65 years of age. No pharmacotherapeutics exist, with surgical repair and transcatheter valve replacement being the only intervention. Females are underrepresented in studies of calcific aortic valve stenosis, leading to delay in timely intervention and increased mortality. Histopathology demonstrates female calcific aortic valve stenosis presents with decreased valvular calcification but increased fibrosis and severity of symptoms. We hypothesize that the underlying molecular mechanisms contributing to disease progression and fibrocalcific burden in aortic stenosis (AS) differ between male and female patients. Our goal for this study is to use previously acquired proteomic data sets of a clinically defined human AS cohort to examine sex disparities and underlying sex-specific disease signatures.</p><p><strong>Methods: </strong>Age-matched human AS tissue samples (n=14 males, n=4 females) were each segmented into nondiseased, fibrotic, and calcified disease stages and analyzed using LC-MS/MS (liquid chromatrophy tandem mass spectrometry) proteomics and quantitative histopathology. AS plasma samples (n=32 males, n=20 females) were analyzed for circulating sex-specific biomarkers via LC-MS/MS.</p><p><strong>Results: </strong>Unbiased principal component analysis shows sex- and stage-specific proteome clustering. AS pathogenesis drove sex-specific disparities in the valvular proteome: 338/1503 total proteins were differentially enriched by sex across disease stages. Compared with sex-specific nondiseased controls, female fibrotic tissue resulted in 2.75-fold greater number of differentially enriched proteins than did male fibrotic tissue (female: 42, male: 16; <i>P</i><0.05 threshold). In contrast, female calcific tissue identified 2.473-fold less differentially enriched proteins than male calcific tissue (female: 157, male 356; <i>P</i><0.05 threshold). Functional Enrichment Analysis revealed specific proteins responsible for the exacerbated valvular fibrosis signature in females, implicated adenosine phosphate metabolism as a potential male-specific driver of AS, and further reinforced the shared contribution of aberrant lipid and cholesterol activity to AS progression in both sexes.</p><p><strong>Conclusions: </strong>This proof-of-concept analysis allows for the identification of potential sex-specific protein drug targets implicated in AS pathobiology.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1928-1934"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844282","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}