{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T19:00:36Z","timestamp":1784746836739,"version":"3.55.0"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>RIP2 (receptor-interacting protein kinase 2) is an essential mediator of inflammation and innate immunity downstream of PRRs (pattern recognition receptors). It is reported that RIP2 is expressed on platelets, while its role in platelet activation, thrombosis, and myocardial infarction, and whether these effects are mediated through the PRR pathway, remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      In vitro assays of platelet aggregation, dense and \u03b1-granule secretion, spreading, and clot retraction, along with an ex vivo microfluidic whole blood perfusion assay, and in vivo models of FeCl\n                      <jats:sub>3<\/jats:sub>\n                      -induced mesenteric arteriolar thrombosis and ischemia\/reperfusion myocardial infarction, were used to assess the impact of RIP2 deficiency on platelet function. Immunoprecipitation followed by liquid chromatography-tandem mass spectrometry was performed to elucidate the mechanism by which RIP2 limits dense granule secretion in platelets. Furthermore, RIP2 expression levels in platelets from healthy donors and patients with coronary artery disease were measured by Western blotting to evaluate their clinical relevance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Here, we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb (platelet glycoprotein Ib) and GPVI (platelet glycoprotein VI) activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time and accelerated FeCl\n                      <jats:sub>3<\/jats:sub>\n                      -induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency worsens myocardial infarction and cardiac function in a mouse ischemia\/reperfusion model. Mechanistically, we found that platelets express DOCK8 (dedicator of cytogenesis protein 8), which is sequestered by p-RIP2 (phosphorylated RIP2), causing inhibition of Cdc42 (cell division cycle 42) activation and subsequent dense granule release.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>RIP2 restrains platelet activation and thrombosis, thereby mitigating myocardial infarction. We identify a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, which suppresses dense granule release downstream of GPIb and GPVI. Targeting the platelet RIP2 pathway may offer a therapeutic strategy against atherothrombotic diseases from early atherosclerosis to arterial thrombosis and myocardial infarction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.323791","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T09:00:34Z","timestamp":1781168434000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Platelet RIP2 Limits Dense Granule Release and Thrombosis via DOCK8-Cdc42"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9689-9898","authenticated-orcid":true,"given":"Jianjun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, China."},{"name":"Department of Clinical Laboratory, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, China (J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, China."},{"name":"MOE-Shanghai Key Laboratory of Children\u2019s Environmental Health, Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital (Z.Z.), Shanghai Jiao Tong University School of Medicine, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4149-150X","authenticated-orcid":true,"given":"Guanxing","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8296-7095","authenticated-orcid":true,"given":"Yangyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China (Y.L., L.H., J.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1878-6155","authenticated-orcid":true,"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-3913","authenticated-orcid":true,"given":"Liang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China (Y.L., L.H., J.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5720-4061","authenticated-orcid":true,"given":"Zhiyong","family":"Qi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease, Zhongshan Hospital (Z.Q.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences (J.Z., Z.Z., G.P., L.C., Y.Z., S.Z., Z.D.), Fudan University, Shanghai, 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