{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:04:06Z","timestamp":1791925446155,"version":"4.3.4"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Communication between the vascular endothelium and peripheral leukocytes is an important process controlling inflammatory responses in the brain. Increased plasma levels of CTSD (cathepsin D) have been associated with vascular events, but whether circulating CTSD may affect the functional status of the endothelium remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      To resolve this issue, two groups of transgenic hCTSD\n                      <jats:sup>hi<\/jats:sup>\n                      mice with high levels of circulating CTSD were subjected to traumatic and ischemic injury, respectively. Then, single\u2010cell RNA sequencing was performed to characterize gene expression changes in the brains of hCTSD\n                      <jats:sup>hi<\/jats:sup>\n                      mice. Additionally, transgenic CTSD\n                      <jats:sup>Mono knockout<\/jats:sup>\n                      mice with reduced plasma CTSD levels were generated to investigate whether CTSD downregulation confers protection against ischemic injury and traumatic brain injury\u2010induced brain damage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We found the hCTSD\n                      <jats:sup>hi<\/jats:sup>\n                      mice showed increased brain neutrophil infiltration in response to the brain injury. Severe motor deficit and delayed behavioral recovery were observed in hCTSD\n                      <jats:sup>hi<\/jats:sup>\n                      mice after brain traumatic and ischemic injury. Mechanistically, the circulating CTSD was characterized as the nonenzymatic prototype CTSD, pro\u2010CTSD. We further found the circulating nonenzymatic pro\u2010CTSD was able to activate brain endothelium by upregulating VCAM\u20101 (vascular cell adhesion molecule 1) expression, which is necessary for the transmigration of neutrophils into the brain. Furthermore, genetic reduction of CTSD effectively attenuated the ischemic injury\u2010induced neutrophil infiltration and motor deficits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Taken together, these results demonstrate that circulating prototype CTSD exacerbates the injury\u2010induced brain damage by upregulating brain endothelial VCAM\u20101 and promoting neutrophil transmigration into the brain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.043416","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T10:49:37Z","timestamp":1761648577000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Circulating Cathepsin D Exacerbates Injury\u2010Induced Brain Damage by Promoting Neutrophil Infiltration Into the Brain"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4321-2766","authenticated-orcid":false,"given":"Yu","family":"Liang","sequence":"first","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zhao","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]},{"name":"the First Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng\u2010Fei","family":"Wu","sequence":"additional","affiliation":[{"name":"the First Affiliated Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6521-452X","authenticated-orcid":false,"given":"Yong\u2010Qi","family":"Liang","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9714-1463","authenticated-orcid":false,"given":"Xue\u2010Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-9806","authenticated-orcid":false,"given":"Jia","family":"Xing","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9384-8013","authenticated-orcid":false,"given":"Xue","family":"Sun","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2730-4484","authenticated-orcid":false,"given":"Ming\u2010Xin","family":"An","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2457-1820","authenticated-orcid":false,"given":"Jun\u2010Xiu","family":"Shi","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4362-2817","authenticated-orcid":false,"given":"Qing\u2010Hua","family":"Gao","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-4864","authenticated-orcid":false,"given":"Li","family":"Tian","sequence":"additional","affiliation":[{"name":"Sheng Jing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-5828","authenticated-orcid":false,"given":"Hong\u2010Zan","family":"Sun","sequence":"additional","affiliation":[{"name":"Sheng Jing Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2713-2156","authenticated-orcid":false,"given":"Bin","family":"Xue","sequence":"additional","affiliation":[{"name":"Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3409-6934","authenticated-orcid":false,"given":"Li\u2010Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Qiqihar Medical University","place":["Qiqihar, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1984-2892","authenticated-orcid":false,"given":"Yu\u2010Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0029-4400","authenticated-orcid":false,"given":"Wei\u2010Dong","family":"Zhao","sequence":"additional","affiliation":[{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00050.2017"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00757-x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012295"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-12-844605"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12443"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.06.007"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.008"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2021.07.002"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2008.02.008"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13060837"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","unstructured":"Laurent\u2010Matha V Huesgen PF Masson O Derocq D Pr\u00e9bois C Gary\u2010Bobo M Lecaille F Rebi\u00e8re B Meurice G Or\u00e9ar C et\u00a0al. Proteolysis of cystatin C by cathepsin D in the breast cancer microenvironment. 2012;26:5172\u20135181. doi: 10.1096\/fj.12-205229","DOI":"10.1096\/fj.12-205229"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr0500197"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.3265\/Nefrologia.pre2014.Oct.12609"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2017.10.005"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-07-6276"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.03.032"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.03.003"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02592-x"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00998"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504640102"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr155"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201910622"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202103098"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110656"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323622"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13170-w"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5286408"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.03.004"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-43093-1_1"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19970601)79:11<2132::AID-CNCR10>3.0.CO;2-X"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1674"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep38278"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-004-0499-3"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10010138"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12920"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-02005-x"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166170"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.02.020"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci117650"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00659.2013"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2014.12.002"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-15805-3"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-85898-9"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9071679"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.32.2.491"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200403078"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00974-6"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abk2552"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-05025-2"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/J.Jhepr.2024.101117"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.987937"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042397"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.123.042714"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11050858"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16670411"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0750-0"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.149179"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053119"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI125116"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2008.05.004"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.125.043416","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:22:34Z","timestamp":1780485754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.125.043416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":61,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2025,11,4]]}},"alternative-id":["10.1161\/JAHA.125.043416"],"URL":"https:\/\/doi.org\/10.1161\/jaha.125.043416","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"2025-05-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e043416"}}