{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T22:28:26Z","timestamp":1785796106488,"version":"3.56.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Sipa1 (signal-induced proliferation-associated gene 1) is known as a specific Rap1 (Ras-related protein 1) GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound-healing response after myocardial infarction (MI) remains unexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both\n              <jats:italic toggle=\"yes\">Sipa1<\/jats:italic>\n              knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast\u2013derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Mice deficient in\n              <jats:italic toggle=\"yes\">Sipa1<\/jats:italic>\n              exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6C (lymphocyte antigen 6 complex, locus C)\n              <jats:sup>high<\/jats:sup>\n              monocytes and CCR (C-C chemokine receptor) 2\n              <jats:sup>+<\/jats:sup>\n              macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast\u2013specific\n              <jats:italic toggle=\"yes\">Sipa1<\/jats:italic>\n              conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL (C-C chemokine ligand) 2, CCL7, and GM-CSF (granulocyte\/macrophage colony-stimulating factor) in the cardiac fibroblasts early after MI via a noncanonical RasGRP2 (Ras guanine nucleotide-releasing protein 2)-Ras-JNK (cellular Jun N-terminal kinase) signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These results identify a previously unknown fibroblast-myeloid axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound-healing response, thereby preventing the development of chronic ischemic heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.326030","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T05:00:22Z","timestamp":1750914022000},"page":"533-547","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Sipa1 Drives a Maladaptive Fibroblast-Myeloid Axis After Myocardial Infarction"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6613-1295","authenticated-orcid":true,"given":"Seien","family":"Ko","sequence":"first","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1025-5725","authenticated-orcid":true,"given":"Yurika","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5580-989X","authenticated-orcid":true,"given":"Genki","family":"Ichihara","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3003-2751","authenticated-orcid":true,"given":"Jin","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."},{"name":"Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Japan (J.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3100-5077","authenticated-orcid":true,"given":"Hiroyuki","family":"Yamakawa","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."},{"name":"Center for Preventive Medicine (H.Y.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohsuke","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisayuki","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., X.L., Y.T., G.I., J.K., H.Y., K.S., H.H., Y.K., J.E., M.S., A.A., M.I.), Keio University School of Medicine, Tokyo, Japan."},{"name":"Suntory Endowed Research Laboratory for Cardiac Regenerative Medicine (H.H.), Keio University School of Medicine, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5576-5789","authenticated-orcid":true,"given":"Yoshinori","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Department of Cardiology 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