{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T13:36:23Z","timestamp":1792503383801,"version":"4.5.0"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2021,12,14]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              LNK\/SH2B3 inhibits Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in\n              <jats:italic>LNK<\/jats:italic>\n              (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that\n              <jats:italic>LNK(TT<\/jats:italic>\n              ) reduces LNK function and that LNK-deficient mice display prominent platelet\u2013neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet\u2013neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic\n              <jats:italic>Lnk<\/jats:italic>\n              deficiency.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We bred mice with combined deficiency of\n              <jats:italic>Lnk<\/jats:italic>\n              and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into\n              <jats:italic>\n                Ldlr\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2\n              <jats:sup>V617F<\/jats:sup>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              <jats:italic>Lnk<\/jats:italic>\n              -deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated\n              <jats:italic>\n                Lnk\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              platelets promoted increased NETosis when incubated with\n              <jats:italic>\n                Lnk\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from\n              <jats:italic>\n                Lnk\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              platelets, as well as increased priming and response of\n              <jats:italic>\n                Lnk\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in\n              <jats:italic>\n                Lnk\n                <jats:sup>\u2013\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              mice. We also showed increased NETosis when human induced pluripotent stem cell\u2013derived\n              <jats:italic>LNK(TT<\/jats:italic>\n              ) neutrophils were incubated with\n              <jats:italic>LNK(TT<\/jats:italic>\n              ) platelet\/megakaryocytes, but not in isogenic\n              <jats:italic>LNK(CC<\/jats:italic>\n              ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2\n              <jats:sup>VF<\/jats:sup>\n              mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic\n              <jats:italic>\n                Lnk\n                <jats:sup>+\/\u2013<\/jats:sup>\n              <\/jats:italic>\n              and\n              <jats:italic>\n                Jak2\n                <jats:sup>VF<\/jats:sup>\n              <\/jats:italic>\n              clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with\n              <jats:italic>\n                Jak2\n                <jats:sup>VF<\/jats:sup>\n                Lnk\n                <jats:sup>+\/+<\/jats:sup>\n              <\/jats:italic>\n              controls.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Hematopoietic\n              <jats:italic>Lnk<\/jats:italic>\n              deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying\n              <jats:italic>\n                Jak2\n                <jats:sup>VF<\/jats:sup>\n              <\/jats:italic>\n              mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.056414","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T19:37:58Z","timestamp":1638301078000},"page":"1940-1954","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":99,"title":["Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency"],"prefix":"10.1161","volume":"144","author":[{"given":"Huijuan","family":"Dou","sequence":"first","affiliation":[{"name":"Molecular Medicine, Columbia University Medical Center, New York (H.D., W.L., T.F., K.E.-U., T.X., S.A., M.Y., B.H., N.W., 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