{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T19:31:03Z","timestamp":1776108663690,"version":"3.50.1"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,4,14]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess the role of Dapk2 in vivo, EC-specific\n                      <jats:italic toggle=\"yes\">Dapk2<\/jats:italic>\n                      -deficient mice on an\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      (apolipoprotein E\n                      <jats:sup>-\/-<\/jats:sup>\n                      ) background were utilized in carotid artery ligation and Western diet\u2013induced atherosclerosis models. Mice with EC-specific overexpression of Pkm2 harboring either a phospho-refractory mutation (Pkm2\n                      <jats:sup>T45A<\/jats:sup>\n                      ) or a phospho-mimicking mutation (Pkm2\n                      <jats:sup>T45E<\/jats:sup>\n                      ) were subjected to carotid artery ligation to further elucidate the functional implications of Pkm2 phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries. Mechanistically, Kr\u00fcppel-like factor 2 (KLF2) suppressed\n                      <jats:italic toggle=\"yes\">DAPK2<\/jats:italic>\n                      transcription, whereas OSS-induced KLF2 downregulation led to DAPK2 upregulation. EC-specific\n                      <jats:italic toggle=\"yes\">Dapk2<\/jats:italic>\n                      deficiency or pharmacological inhibition suppressed EC activation and atherogenesis in\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice, effects reversed by overexpression of wild-type Dapk2 but not by a dominant-negative mutant. Mass spectrometry identified that DAPK2 interacted with the key glycolytic enzyme PKM2 and directly phosphorylated it at threonine 45, leading to PKM2 dimerization and nuclear translocation. Nuclear PKM2 activated the expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 by directly interacting with and activating signal transducer and activator of transcription 1. Elevated PKM2\n                      <jats:sup>T45<\/jats:sup>\n                      and signal transducer and activator of transcription 1\n                      <jats:sup>Y701<\/jats:sup>\n                      phosphorylation were observed in atheroprone endothelium. Finally, EC-specific overexpression of Pkm2\n                      <jats:sup>T45A<\/jats:sup>\n                      mitigated disturbed flow-induced atherogenesis, whereas Pkm2\n                      <jats:sup>T45E<\/jats:sup>\n                      overexpression abrogated the protective effects of\n                      <jats:italic toggle=\"yes\">Dapk2<\/jats:italic>\n                      deficiency in\n                      <jats:italic toggle=\"yes\">Apoe<\/jats:italic>\n                      <jats:sup>-\/-<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.075951","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T10:00:15Z","timestamp":1769767215000},"page":"1117-1140","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["DAPK2 Regulates PKM2 Phosphorylation at Threonine 45 to Facilitate Disturbed Flow-Induced Atherosclerosis"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-5516","authenticated-orcid":true,"given":"Shuai","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."},{"name":"BHF Centre for Cardiovascular Science, Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom (S.G., A.H.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3487-3929","authenticated-orcid":true,"given":"Long","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China (Y.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runfa","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3294-9582","authenticated-orcid":true,"given":"Kaixiang","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pathology, People\u2019s Hospital of Jiangxi Province, Nanchang, China (K.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7142-456X","authenticated-orcid":true,"given":"Litao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University; State Key Laboratory of Transvascular Implantation Devices, Hangzhou, China (L.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjia","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (W.A.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9087-227X","authenticated-orcid":true,"given":"Jiang-yun","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (J.-y.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9457-0164","authenticated-orcid":true,"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China (L.L., J.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"He","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China (L.L., J.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5685-066X","authenticated-orcid":true,"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing, China (Y. Zhou)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-8092","authenticated-orcid":true,"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China (L.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-5576","authenticated-orcid":true,"given":"Andrew H","family":"Baker","sequence":"additional","affiliation":[{"name":"BHF Centre for Cardiovascular Science, Institute for Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh, United Kingdom (S.G., A.H.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-4122","authenticated-orcid":true,"given":"Yuqing","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Medicine (Section of Cardiovascular Research), Baylor College of Medicine, Houston, TX (Y.H.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8866-7859","authenticated-orcid":true,"given":"Yiming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.)."},{"name":"Department of Emergency, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China (Y.X.)."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2024.107368"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0106-z"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00276-0"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108152"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00883-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20602"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.321322"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-08-3465"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316857"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2023.102216"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-278192"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.03.065"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0813462"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108491"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120912"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000001568"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2629"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10598"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.01.001"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.12.005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab152"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.002714"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.318690"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102103"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.314402"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309249"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-024-00523-y"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10020254"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.525774"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.11.004"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvae071"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.04.025"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22797"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.06.017"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102693"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311249111"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2010.02.018"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22975"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.200337"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2424796122"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering11040325"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2424566122"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.121.316021"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.320704"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.177"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6566"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000431"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.09.004"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2318904121"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15926"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-025-01259-0"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.325049"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202406184"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000205850.49390.3b"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.499095"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.114198"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaf233"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2022.11673"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.125.326409"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.872663"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.92.12.3431"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.54"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.321187"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1059"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky427"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky357"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac394"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.125.075951","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:00:25Z","timestamp":1776103225000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.125.075951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":68,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2026,4,14]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.125.075951"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.125.075951","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"assertion":[{"value":"2025-06-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}