{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:13:03Z","timestamp":1788858783485,"version":"build-2803163510"},"reference-count":79,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"abstract":"\n BACKGROUND:<\/jats:title>\n Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering\u2013induced plaque remodeling or regression has not been extensively studied.<\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric\n Tet2<\/jats:italic>\n \n +\/<\/jats:italic>\n -\n <\/jats:sup>\n CH mice with conditional deletion of\n Tet2<\/jats:italic>\n in hematopoietic stem cells during LDL lowering\u2013induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in\n Ldlr<\/jats:italic>\n \n -\/<\/jats:italic>\n -\n <\/jats:sup>\n mice,\n Tet2<\/jats:italic>\n was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n Unlike control mice,\n Tet2<\/jats:italic>\n \n +\/<\/jats:italic>\n -\n <\/jats:sup>\n CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that\n Tet2<\/jats:italic>\n deficient monocyte\/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization.\n Tet2<\/jats:italic>\n -deficient bone marrow\u2013derived macrophages and\n Tet2<\/jats:italic>\n \n +\/<\/jats:italic>\n -\n <\/jats:sup>\n induced pluripotent stem cell\u2013derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow\u2013derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1\u03b1 (hypoxia-inducible factor 1\u03b1) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering\u2013induced plaque remodeling in\n Tet2<\/jats:italic>\n \n +\/<\/jats:italic>\n -\n <\/jats:sup>\n CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n \n Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with\n TET2<\/jats:italic>\n CH.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circulationaha.126.080527","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:02:32Z","timestamp":1788858152000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in\n Tet2<\/i>\n Clonal 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