{"doi":"10.1161/jaha.125.046482","title":"Monocytes Defined by Platelet Interactions and Oxidative Stress Signaling Underlie HIV‐Associated Atherosclerosis","abstract":"\n Background\n Monocytes contribute to atherosclerosis by migrating into inflamed endothelium and differentiating into lipid‐laden macrophages. In people living with HIV, chronic inflammation increases atherosclerosis risk, yet the role of specific monocyte subsets remains unclear. We investigated how distinct monocyte populations contribute to vascular pathology in early HIV‐associated atherosclerosis.\n \n \n Methods\n We profiled 123 965 circulating monocytes using single‐cell RNA sequencing and integrated plasma microparticle proteomics in 32 individuals stratified by HIV and atherosclerosis status. Supervised learning identified cluster‐ and disease‐specific signatures, validated by platelet‐monocyte cocultures, reverse transcription–quantitative polymerase chain reaction, bulk RNA sequencing, flow cytometry, and ELISA.\n \n \n Results\n \n Seven monocyte clusters were identified, including a subset characterized by platelet–monocyte complexes. Bulk RNA sequencing of platelet–monocyte cocultures revealed platelet‐driven upregulation of genes involved in inflammation, lipid metabolism, oxidative stress, and endothelial adhesion. Platelet–monocyte complex–derived macrophages secreted higher levels of TGF‐β (transforming growth factor‐β) and IL‐10 (interleukin‐10), displayed decreased CD14 and increased CD80/CD86 while retaining CD36, and promoted endothelial‐to‐mesenchymal transition (decreased expression of\n CDH5\n and\n PECAM1\n ; increased expression of\n S100A4\n and markers of vascular inflammation (\n ICAM1\n ),\n VCAM\n ), and IL‐6 (interleukin‐6), and CCL2 (C‐C motif chemokine ligand 2) secretion). Additionally, CD14\n +\n monocytes from HIV\n +\n atherosclerosis‐negative and HIV\n +\n atherosclerosis‐positive groups showed enhanced ROS‐NRF2 (reactive oxygen species–nuclear factor erythroid 2–related factor 2) pathway activities, supported by increased basal and H\n 2\n O\n 2\n ‐induced p90RSK phosphorylation, indicating oxidative stress priming.\n \n \n \n Conclusions\n \n Two monocyte clusters contribute independently to vascular immune dysregulation in people living with HIV. Platelet–monocyte complex–derived macrophages promote endothelial dysfunction while adopting a profibrotic cytokine profile. CD14\n +\n monocytes show heightened oxidative signaling and stress responses, consistent with vascular activation. Together, these mechanisms may accelerate atherosclerosis development in HIV, even in the absence of traditional cardiovascular risk factors.\n \n ","journal":"Journal of the American Heart Association","year":2026,"id":642247,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1169377,"name":"Zachary D. Boodoo","orcid":"0000-0002-1641-4406","position":1,"is_corresponding":false},{"id":1169376,"name":"Karli R. Sutton","orcid":"0009-0002-5370-9809","position":2,"is_corresponding":false},{"id":1670334,"name":"Sengathir Rajagopal","orcid":"0009-0008-9562-4444","position":3,"is_corresponding":false},{"id":449040,"name":"Jun‐ichi Abe","orcid":"0000-0001-7439-7774","position":4,"is_corresponding":false},{"id":368420,"name":"Sanjay B. Maggirwar","orcid":"0000-0003-4948-917X","position":5,"is_corresponding":false},{"id":282105,"name":"Giovanni Schifitto","orcid":"0000-0002-2115-4143","position":6,"is_corresponding":false},{"id":368414,"name":"Meera V. Singh","orcid":"0000-0001-8481-1668","position":7,"is_corresponding":false},{"id":408836,"name":"Juilee Thakar","orcid":"0000-0003-4479-4183","position":8,"is_corresponding":false},{"id":703114,"name":"Ruoqiao Huiyi Wang","orcid":"0000-0003-2013-4850","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Monocytes Defined by Platelet Interactions and Oxidative Stress Signaling Underlie HIV‐Associated Atherosclerosis","abstract":"\n Background\n Monocytes contribute to atherosclerosis by migrating into inflamed endothelium and differentiating into lipid‐laden macrophages. In people living with HIV, chronic inflammation increases atherosclerosis risk, yet the role of specific monocyte subsets remains unclear. We investigated how distinct monocyte populations contribute to vascular pathology in early HIV‐associated atherosclerosis.\n \n \n Methods\n We profiled 123 965 circulating monocytes using single‐cell RNA sequencing and integrated plasma microparticle proteomics in 32 individuals stratified by HIV and atherosclerosis status. Supervised learning identified cluster‐ and disease‐specific signatures, validated by platelet‐monocyte cocultures, reverse transcription–quantitative polymerase chain reaction, bulk RNA sequencing, flow cytometry, and ELISA.\n \n \n Results\n \n Seven monocyte clusters were identified, including a subset characterized by platelet–monocyte complexes. Bulk RNA sequencing of platelet–monocyte cocultures revealed platelet‐driven upregulation of genes involved in inflammation, lipid metabolism, oxidative stress, and endothelial adhesion. Platelet–monocyte complex–derived macrophages secreted higher levels of TGF‐β (transforming growth factor‐β) and IL‐10 (interleukin‐10), displayed decreased CD14 and increased CD80/CD86 while retaining CD36, and promoted endothelial‐to‐mesenchymal transition (decreased expression of\n CDH5\n and\n PECAM1\n ; increased expression of\n S100A4\n and markers of vascular inflammation (\n ICAM1\n ),\n VCAM\n ), and IL‐6 (interleukin‐6), and CCL2 (C‐C motif chemokine ligand 2) secretion). Additionally, CD14\n +\n monocytes from HIV\n +\n atherosclerosis‐negative and HIV\n +\n atherosclerosis‐positive groups showed enhanced ROS‐NRF2 (reactive oxygen species–nuclear factor erythroid 2–related factor 2) pathway activities, supported by increased basal and H\n 2\n O\n 2\n ‐induced p90RSK phosphorylation, indicating oxidative stress priming.\n \n \n \n Conclusions\n \n Two monocyte clusters contribute independently to vascular immune dysregulation in people living with HIV. Platelet–monocyte complex–derived macrophages promote endothelial dysfunction while adopting a profibrotic cytokine profile. CD14\n +\n monocytes show heightened oxidative signaling and stress responses, consistent with vascular activation. Together, these mechanisms may accelerate atherosclerosis development in HIV, even in the absence of traditional cardiovascular risk factors.\n \n ","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41823228","pmcid":"PMC13055746","openalex_id":"https://openalex.org/W7135172778","authors":[],"funders":[{"funder_name":"NIA NIH HHS","grant_id":"R01 AG077156","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL123346","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"R21 AI162076","title":null},{"funder_name":"NHLBI NIH HHS","grant_id":"R01 HL160229","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS131062","title":null}],"total_grants":5,"fwci":0.0,"citation_percentile":0.25418892,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1161/jaha.125.046482","host_type":"journal"},{"url":"https://doi.org/10.1161/jaha.125.046482","host_type":"publisher"},{"url":"https://www.ahajournals.org/doi/full/10.1161/JAHA.125.046482","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41823228","host_type":"repository"},{"url":"https://doaj.org/article/9a02fb24f9d44b38a5acc4b68c8140f3","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13055746/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC13055746","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC13055746?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["HIV-related health complications and treatments","Platelet Disorders and Treatments","Immune cells in cancer"],"mesh_terms":["Adult","Blood Platelets","Female","Humans","Macrophages","Male","Middle Aged","Monocytes","Signal Transduction","HIV Infections","Oxidative Stress","Atherosclerosis"],"keywords":["Oxidative stress","Monocyte","Endothelial dysfunction","Platelet","Immune system","Platelet activation","Inflammation","Cytokine","Immune dysregulation","Signal transduction","Atherosclerosis","HIV","Single‐cell Rna Sequencing"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T22:05:53.130939Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}