{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:33:31Z","timestamp":1791268411455,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,3,27]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Janus kinase\/signal transducer and activator of transcription (JAK\/STAT) signals and their endogenous inhibitor, suppressor of cytokine signaling 3 (SOCS3), in vascular endothelial cells (ECs) reportedly dominate the pathological angiogenesis. However, how these inflammatory signals are potentiated during pathological angiogenesis has not been fully elucidated. We suspected that an intracellular protease calpain, which composes the multifunctional proteolytic systems together with its endogenous inhibitor calpastatin (CAST), contributes to the JAK\/STAT regulations.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To specify the effect of EC calpain\/CAST systems on JAK\/STAT signals and their relationship with pathological angiogenesis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              The loss of CAST, which is ensured by several growth factor classes, was detectable in neovessels in murine allograft tumors, some human malignant tissues, and oxygen-induced retinopathy lesions in mice. EC-specific transgenic introduction of\n              <jats:italic>CAST<\/jats:italic>\n              caused downregulation of JAK\/STAT signals, upregulation of SOCS3 expression, and depletion of vascular endothelial growth factor (VEGF)-C, thereby counteracting unstable pathological neovessels and disease progression in tumors and oxygen-induced retinopathy lesions in mice. Neutralizing antibody against VEGF-C ameliorated pathological angiogenesis in oxygen-induced retinopathy lesions. Small interfering RNA\u2013based silencing of endogenous\n              <jats:italic>CAST<\/jats:italic>\n              in cultured ECs facilitated \u03bc-calpain\u2013induced proteolytic degradation of SOCS3, leading to VEGF-C production through amplified interleukin-6\u2013driven STAT3 signals. Interleukin-6\u2013induced angiogenic tube formation in cultured ECs was accelerated by\n              <jats:italic>CAST<\/jats:italic>\n              silencing, which is suppressible by pharmacological inhibition of JAK\/STAT signals, antibody-based blockage of VEGF-C, and transfection of calpain-resistant SOCS3, whereas transfection of wild-type SOCS3 exhibited modest angiostatic effects.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Loss of CAST in angiogenic ECs facilitates \u03bc-calpain\u2013induced SOCS3 degradation, which amplifies pathological angiogenesis through interleukin-6\/STAT3\/VEGF-C axis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.305363","type":"journal-article","created":{"date-parts":[[2015,2,4]],"date-time":"2015-02-04T03:21:13Z","timestamp":1423020073000},"page":"1170-1181","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Calpastatin Counteracts Pathological Angiogenesis by Inhibiting Suppressor of Cytokine Signaling 3 Degradation in Vascular Endothelial Cells"],"prefix":"10.1161","volume":"116","author":[{"given":"Takuro","family":"Miyazaki","sequence":"first","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Taketomi","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Saito","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Hosono","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Lei","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo-ri","family":"Kim-Kaneyama","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Arata","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruo","family":"Takahashi","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Murakami","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"From the Department of Biochemistry (T.M., X.-F.L., J.-r.K.-K., A.M.), Department of Ophthalmology (Y.S., H.T.), Showa University School of Medicine, Tokyo, Japan; Center for Biotechnology, Showa University, Tokyo, Japan (T.H., S.A.); and Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan (Y.T., M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10144"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.01.089"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04482"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-108597"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-04-422527"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0623"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70683"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205260"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.183"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.290841"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000209968.66606.10"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2002"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.14787"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2010.08.008"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804628200"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.021675"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.2.552"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1275"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00083.2007"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.03.024"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16808"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0603-669"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2331"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199812)177:3<439::AID-JCP7>3.0.CO;2-2"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02966957"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0898-915"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.1604.13.10"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(19990219)84:1<6::AID-IJC2>3.0.CO;2-T"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22638"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060469"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.2006.101543"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.061018"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1097\/IAE.0b013e31816576d5"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.116.305363","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T03:42:12Z","timestamp":1715571732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.116.305363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,27]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,3,27]]}},"alternative-id":["10.1161\/CIRCRESAHA.116.305363"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.116.305363","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,27]]},"assertion":[{"value":"2014-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-02-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-02-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}