Circulation research最新文献

{"title":"Proteogenomics of Hypertrophic Cardiomyopathy Reveals Subtype-Specific Therapy.","authors":"Ke Ma, Jie Yang, Hongchang Guo, Ping Li, Xiaowei Li, Zhujun Dong, Jing Zhang, Congcong Zhang, Pengli Yang, Chongpei Hua, Shuolin Zhu, Guoqing Li, Jianchao Zhang, Ningyu Ding, Jizheng Wang, Xin-Liang Ma, Zhuofeng Lin, Jianzeng Dong, Yang Li, Yulin Li","doi":"10.1161/CIRCRESAHA.126.328300","DOIUrl":"10.1161/CIRCRESAHA.126.328300","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with diverse prognosis. The underlying mechanisms remain unknown, resulting in limited risk stratification and therapeutic strategies. This study aimed to elucidate molecular subtypes of HCM through integrated proteogenomic analysis and explore subtype-specific therapeutic strategies.</p><p><strong>Methods: </strong>We conducted an integrated proteogenomic analysis of 132 patients with HCM using myocardial samples, incorporating whole-exome sequencing, RNA sequencing, and proteomics. Unsupervised clustering was used to identify HCM subtypes, which were validated in heart tissues and human induced pluripotent stem cell-derived cardiomyocytes from 2 independent HCM subsets. Subtype-specific signatures and pathways were explored, and their causal link with HCM pathogenesis was established by genetic evidence. A subtype-specific drug was screened using in silico drug prediction, followed by in vitro and in vivo therapeutic effect assessments.</p><p><strong>Results: </strong>Integrated multi-omics analysis identified 2 proteome-based molecular subtypes, severe and mild. We identified 550 subtype-signature proteins, and enrichment analysis based on which revealed that the reduction in fatty acid metabolism and oxidative phosphorylation pathways in HCM versus healthy controls was predominantly driven by the severe subtype, with more severe clinical characteristics and poorer prognosis compared with the mild subtype. Validation in independent cohorts confirmed the robustness of the proteomic subtypes and their association with clinical severity. Additionally, key proteins in fatty acid oxidation and oxidative phosphorylation exhibited consistent expression differences among healthy controls and 2 HCM subtypes. Furthermore, genetic evidence established a causal link between reduced fatty acid oxidation and HCM pathogenesis. Baicalin, identified as a fatty acid oxidation facilitator, improved metabolic and hypertrophic phenotypes in severe subtype human induced pluripotent stem cell-derived cardiomyocytes and Myh6^R404Q/+ mice.</p><p><strong>Conclusions: </strong>Our analysis demonstrates the metabolic heterogeneity of HCM and enables the development of risk stratification and subtype-specific therapeutic strategies.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03076580.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328300"},"PeriodicalIF":18.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359465","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":"Increased Autoreactive CD8+ T Cells to Apolipoprotein B Epitopes in Patients With Severe Coronary Artery Disease.","authors":"Payel Roy,Smriti Parashar,John Sidney,Megh Mehta,Ishita Tandon,Margaret Beddall,Yan Wang,Irina Baranovskaya,Andrew Soo Hoo,Ralph Ierardi,Gautam Agarwal,William D Jordan,Coleen A McNamara,Alessandro Sette,Hossam Abdelsamed,Klaus Ley","doi":"10.1161/circresaha.125.326804","DOIUrl":"https://doi.org/10.1161/circresaha.125.326804","url":null,"abstract":"BACKGROUNDAtherosclerosis is a chronic inflammatory disease with a strong autoimmune component, marked by the detection of autoreactive T cells and autoantibodies. Recent single-cell RNA sequencing studies have shown that atherosclerotic plaques contain clonally expanded CD8+ T cells. One of the known atherosclerosis autoantigens is APOB (apolipoprotein B). However, autoreactive CD8+ T cells to APOB in humans have not been described.METHODSWe studied CD8+ T-cell reactivity to human leukocyte antigen-A*02:01-restricted APOB epitopes, starting with in silico epitope prediction. We used peripheral blood mononuclear cells from human leukocyte antigen-A02:01+ healthy subjects to test the top 64-ranked peptides for their potential to elicit a CD8+ T-cell response. Antigen-specific responses were assessed using activation-induced marker assays, intracellular cytokine staining, and IFNγ (interferon gamma) ELISpot assays.RESULTSSome APOB peptides triggered robust CD8+ T-cell activation with effector memory features, and expression of cytokines and cytotoxic molecules. Five immunodominant epitopes spanning 2 APOB regions accounted for most of the response and elicited significant T-cell activation in healthy donors that was increased in clinical samples from patients with severe coronary artery disease.CONCLUSIONSThe discovery of immunodominant major histocompatibility complex class I-restricted APOB epitopes suggests a new perspective for immune-based interventions to mitigate atherosclerosis.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"12 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552571","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":"Tertiary Lymphoid Structures and CXCL13 as Targets in Intracranial Aneurysm.","authors":"Zhiyao Zheng,Zishuo Lu,Ziliang Han,Qiheng He,Nan Wang,Xin Zhang,Peicong Ge,Jia Li,Bojian Zhang,Xinyu Ma,Yu Wang,Qian Zhang,Xun Ye,Wenbin Ma,Hao Li,Jizong Zhao","doi":"10.1161/circresaha.125.328094","DOIUrl":"https://doi.org/10.1161/circresaha.125.328094","url":null,"abstract":"BACKGROUNDIntracranial aneurysms (IAs) are localized dilations of cerebral arteries that pose a significant threat of rupture, leading to fatal subarachnoid hemorrhage. The inflammation driven by immune cell infiltration is believed to be a key driver for the pathogenesis of IAs; however, the detailed immune cell landscape and spatial composition of immune cells remain unclear.METHODSIn this study, we employed an integrated multi-omics approach using human IA tissues, including single‑cell RNA sequencing, spatial transcriptomics, microarray data, and multiplex immunofluorescence, to construct a comprehensive immune cell atlas of IAs, providing a systematic characterization of their immune composition and spatial architecture. Findings were further validated in a mouse model of IA.RESULTSWe identified, for the first time, tertiary lymphoid structures within the aneurysm wall and demonstrated that their presence strongly correlates with rupture. Furthermore, we observed a significant expansion of a specific T-cell subset, CXCL13+ T-follicular helper cells. These cells were critical for B-cell recruitment and the structural organization of the tertiary lymphoid structures. In the IA mouse model, CXCL13 neutralization effectively suppressed both aneurysm formation and rupture.CONCLUSIONSOur finding establishes tertiary lymphoid structures and CXCL13+ T follicular helper cells as central elements in IA progression and highlight the CXCL13 signaling axis as a promising therapeutic target for preventing aneurysm advancement.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"149 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148522185","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":"Small Extracellular Vesicles From Cardiomyocytes Activate Microglia Aggravating HFpEF.","authors":"Lintong Men,Qian Wang,Bowen Ren,Yu Cao,Min Du,Shengqi Huo,Moran Wang,Bingyu Huang,Dewei Peng,Xiaoli He,Lujin Wu,Sheng Li,Cuntai Zhang,Jiaogao Lv,Li Lin,Junyi Guo","doi":"10.1161/circresaha.125.327765","DOIUrl":"https://doi.org/10.1161/circresaha.125.327765","url":null,"abstract":"BACKGROUNDHeart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored.METHODS AND RESULTSWe constructed an HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (N[ω]-nitro-l-arginine methyl ester). These mice exhibited microglial activation and hypothalamic inflammation. Microglial depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEV biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid-treated HL-1 cardiomyocytes, as well as in microglia. A cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, a miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while a miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. The antiinflammatory protein DUSP1 (dual-specificity phosphatase 1) was validated as a potential downstream target of miR-200c-3p in microglia.CONCLUSIONSOur study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"34 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148499002","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":"Glycine Receptor α2 Mediates Vasodilation via Endothelial eNOS Signaling.","authors":"Xueya Bai, Yan Wang, Wenying Zhou, Yueqi Yu, Yan Dai, Jinhao Li, Qinghua Chen, Wei Hou, Xiqi Zhu, Hui Bai, Qing Yang, Bin Jiang, Jingjing Ben, Hanwen Zhang, Xiaoyu Li, Chao Lu, Xiaolin Miao, Jian Xu, Nan Jiang, Juejin Wang, Steven Y Cheng, Xudong Zhu, Qi Chen","doi":"10.1161/CIRCRESAHA.126.328205","DOIUrl":"10.1161/CIRCRESAHA.126.328205","url":null,"abstract":"<p><strong>Background: </strong>Endothelium-derived NO is an important vasodilator essential for maintaining vascular homeostasis. However, how eNOS (endothelial nitric oxide synthase) is regulated in hypertension conditions is not yet fully understood. In this study, we describe a critical role of the GLRA2 (α2 subunit of glycine receptor) in modulating eNOS signaling and blood pressure regulation.</p><p><strong>Methods: </strong>Endothelial-specific <i>Glra2</i>-deficient mice and the adeno-associated viral-transfected mice were generated to assess the role of GLRA2 in hypertension models. Endothelium-dependent relaxation response and whole-cell patch clamp recording were determined.</p><p><strong>Results: </strong>We first demonstrated selective expression of GLRA2 in arterial endothelial cells. Activation of GLRA2 by its ligand, glycine, effectively counteracts hypertension in a GLRA2-dependent manner. Our patient study indicated a negative correlation between plasma levels of glycine and blood pressure. Furthermore, we showed that endothelial GLRA2 regulates vasodilation by promoting NO production, rather than functioning solely as a chloride channel. Mechanistically, GLRA2 facilitates the phosphorylation of glycogen synthase kinase-3β at Ser9 (serine 9), which activates the AKT (protein kinase B)/eNOS signaling pathway in the endothelium, leading to increased NO release.</p><p><strong>Conclusions: </strong>This study discovers that a novel endothelial GLRA2 pathway holds significant potential for developing new strategies to control hypertension.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328205"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276314","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":"Endothelial Estrogen Receptor Alpha Inhibits Plaque Inflammation in Both Sexes.","authors":"Nicole L Svedberg, Qing Lu, Alec Stepanian, Wenxi An, Sorelle Tan, Joshua J Man, Iris Z Jaffe","doi":"10.1161/CIRCRESAHA.126.328735","DOIUrl":"10.1161/CIRCRESAHA.126.328735","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerotic plaque inflammation correlates with risk of rupture, causing myocardial infarction. Lower myocardial infarction risk in young women compared with men abates post-menopause, implicating ERs (estrogen receptors). The ERa (ER alpha) is necessary for estrogen effects on atherosclerosis in mouse models, yet the mechanistic role of ERa in plaque inflammation in both sexes remains unclear.</p><p><strong>Methods: </strong>The role of ERa in driving endothelial cell (EC) adhesion molecule expression and inflammation was studied in vitro in primary human ECs and in vivo in mice. LDLR (low-density lipoprotein receptor)-knockout mice with EC-specific ERa knockout were compared with ERa-intact littermates after 12 weeks of high-fat diet.</p><p><strong>Results: </strong>In both sexes, EC-specific ERa knockout increased plaque inflammation and expression of adhesion molecules, including ICAM1 (intracellular adhesion molecule 1). In vitro, primary human ECs from young women expressed more ERa and less ICAM1 versus age-matched cells from men. ERa knockdown in human coronary ECs from both sexes increased adhesion molecules. Because the MR (mineralocorticoid receptor) has been implicated in ICAM1 expression and plaque inflammation in males, the impact of ERa on MR-induced ICAM1 expression was explored. In human ECs, estrogen prevented aldosterone induction of ICAM1 and MR enrichment on the ICAM1 promoter. In vivo, EC-specific MR-knockout and EC-ERa/MR-double-knockout/LDLR-knockout mice were studied as above. In females, EC-specific MR knockout did not impact ICAM1 or plaque inflammation, consistent with ERa inhibiting MR function. In the double-knockout model, the lack of MR prevented the increased inflammation and ICAM1 expression observed with loss of EC-ERa. In males, EC-specific MR knockout alone decreased inflammation and ICAM1. In the double-knockout model, the proinflammatory effects of MR and the anti-inflammatory impact of ERa offset each other.</p><p><strong>Conclusions: </strong>These findings reveal a role for ERa in regulating plaque inflammation in both sexes. In females, estrogen acts via EC-ERa to inhibit MR transcriptional upregulation of ICAM1, attenuating plaque inflammation. In males, ICAM1 expression is driven by the MR and inhibited by ERa.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e328735"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210429","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000762","DOIUrl":"https://doi.org/10.1161/RES.0000000000000762","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 3","pages":"e000762"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469327","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":"Correction to: Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption.","authors":"Georgia Zarkada, Xun Chen, Xuetong Zhou, Martin Lange, Lei Zeng, Wenyu Lv, Xuan Zhang, Yunhua Li, Weibin Zhou, Keli Liu, Dongying Chen, Nicolas Ricard, James Liao, Young-Bum Kim, Rui Benedito, Lena Claesson-Welsh, Kari Alitalo, Michael Simons, Rong Ju, Xuri Li, Anne Eichmann, Feng Zhang","doi":"10.1161/RES.0000000000000761","DOIUrl":"https://doi.org/10.1161/RES.0000000000000761","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"139 3","pages":"e000761"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469245","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":"Inflammasome-Primed Neutrophils Aggravate Atherosclerosis in Cigarette Smoking.","authors":"Dipanjan Chattopadhyay, Nitin Nitin, Robert M Jaggers, Baskaran Athmanathan, Krishna P Maremanda, Babunageswararao Kanuri, Albert Dahdah, Rajnikant Shukla, Man S K Lee, Andrew J Murphy, Prabhakara R Nagareddy","doi":"10.1161/CIRCRESAHA.125.327714","DOIUrl":"10.1161/CIRCRESAHA.125.327714","url":null,"abstract":"<p><strong>Background: </strong>Cigarette smoking (CS) is a major risk factor for cardiovascular disease through chronic inflammation. While its pulmonary effects are well established, the mechanisms linking lung inflammation to vascular injury remain unclear. Because neutrophils are early responders to CS-induced inflammation, we hypothesized that they drive systemic myelopoiesis and vascular inflammation via alarmin release.</p><p><strong>Methods: </strong>Wild-type mice were exposed to inhaled CS or orally administered cigarette smoke extract. Immune cell composition in lung, bronchoalveolar lavage fluid, blood, spleen, and bone marrow was assessed by flow cytometry. Hematopoietic stem and progenitor cell proliferation, reactive oxygen species production, and S100A8/A9 (S100 calcium-binding protein A8/A9) release were quantified. Atherosclerosis progression was evaluated in <i>Ldlr^-/-</i> (low-density lipoprotein receptor-deficient) mice fed a Western diet and treated with cigarette smoke extract. To define the role of neutrophil-derived S100A8/A9, bone marrow transplantation was performed using <i>S100a9</i>^<i>-/-</i> or wild-type donors.</p><p><strong>Results: </strong>CS exposure increased circulating monocytes and neutrophils through enhanced bone marrow myelopoiesis and elevated reactive oxygen species-dependent S100A8/A9 release. Oral cigarette smoke extract reproduced these effects, indicating direct activation of neutrophils independent of pulmonary inflammation or lipid changes. In <i>Ldlr</i>^<i>-/-</i> mice, cigarette smoke extract accelerated atherosclerosis by promoting infiltration of inflammasome-primed neutrophils, increasing IL-1β (interleukin 1 beta) release, and impairing macrophage efferocytosis. Hematopoietic <i>S100a9</i> deletion normalized myelopoiesis and reduced vascular inflammation and plaque burden.</p><p><strong>Conclusions: </strong>Ingested CS components directly activate neutrophils to release S100A8/A9, triggering myelopoiesis and vascular inflammation. These findings reveal that tobacco's cardiovascular toxicity extends beyond inhalation, implicating oral exposure as a driver of systemic inflammation and atherogenesis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e327714"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148210471","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":"Monocyte Dll4 Contributes to Systemic Inflammation in People Living With HIV.","authors":"Shumin Wang, Meera V Singh, Craig N Morrell, Hongmei Yang, Jordan Rhen, Tengge Wang, Laith Awad Mohamad, Jasmine Jiayuan Xu, Tiffany Nguyen, Sara Ture, Alicia Tyrell, Jinghan Zhang, Sanjay B Maggirwar, Giovanni Schifitto, Jinjiang Pang","doi":"10.1161/CIRCRESAHA.125.326836","DOIUrl":"10.1161/CIRCRESAHA.125.326836","url":null,"abstract":"<p><strong>Background: </strong>In people living with HIV (PLWH), persistent systemic inflammation drives comorbidities, including cardiovascular and cerebrovascular diseases. Monocyte-mediated inflammation, rather than T-cell activation, is a major contributor to chronic inflammation. However, the underlying mechanisms remain elusive. Here, we investigated the role of Dll4 (delta-like 4)-Notch signaling in monocyte-mediated inflammation.</p><p><strong>Methods: </strong>In clinical specimens, we quantified monocyte mDll4 (membrane-bound Dll4) expression and plasma levels of exDll4 (extracellular Dll4). We also analyzed the association between circulating exDll4 and monocyte subsets in PLWH. In vitro, human primary monocytes, endothelial cells, and T cells were stimulated with lipopolysaccharide or TNF-α (tumor necrosis factor-α) to assess <i>DLL4</i> mRNA and Dll4 protein expression and exDll4 secretion. RNA sequencing was performed after <i>DLL4</i> silencing to determine downstream signaling pathways. In addition, molecular and functional studies examined the effects of Dll4-Notch1 signaling on interferon-related gene expression, monocyte adhesion, and transmigration.</p><p><strong>Results: </strong>Both male and female PLWH exhibited significantly increased mDll4 expression, activation of Dll4-Notch1 signaling, and increased Notch-targeted inflammatory factors. Although monocyte mDll4 did not differ by sex in PLWH, plasma exDll4 was significantly elevated in males, but not females, compared with HIV-uninfected individuals. In male PLWH, plasma exDll4 levels paralleled monocyte mDll4 expression. Circulating exDll4 was positively associated with proinflammatory monocytes and negatively associated with classical monocytes in male PLWH. Mechanistically, lipopolysaccharide or TNF-α robustly increased <i>DLL4</i> mRNA and protein expression in human primary monocytes, along with exDll4 secretion from monocytes, but not from endothelial cells or T cells. RNA sequencing after <i>DLL4</i> silencing showed that Dll4-Notch signaling suppresses a broad anti-pathogen program regulated by interferon and NF-κB, as well as cell-mobility-related genes. At the molecular level, Dll4 activated Notch1, which upregulated Hes1, forming a heterotrimer with STATs (signal transducers and activators of transcription), and repressed interferon pathway-related gene expression. Functionally, loss of Dll4 significantly reduced monocyte adhesion and transmigration.</p><p><strong>Conclusions: </strong>Proinflammatory cues upregulate Dll4 in monocytes and activate Dll4-Notch signaling, thereby suppressing antiviral responses and enhancing monocyte transmigration. Together, these effects sustain systemic inflammation in PLWH of both sexes. Our data identify monocyte-derived Dll4 as a promising biomarker and therapeutic target for systemic inflammation.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e326836"},"PeriodicalIF":18.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223770","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}