{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:04:17Z","timestamp":1792458257974,"version":"4.5.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The ROR\u03b3t (nuclear receptor retinoid\u2010related orphan receptor \u03b3t) has been identified as a master transcription factor critical for the differentiation of T helper 17 cells, the primary source of IL\u201017A (interleukin\u201017A). We previously demonstrated that IL\u201017A promotes neuroinflammation and sympathetic excitation, contributing to cardiac dysfunction in heart failure and angiotensin II (ANG II)\u2010induced hypertension. The present study sought to determine whether inhibiting ROR\u03b3t, thereby reducing IL\u201017A production, could attenuate microglial activation, neuroinflammation, and sympathetic excitation by preserving the integrity of the blood\u2013brain barrier (BBB) in ANG II\u2010induced hypertensive rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Rats underwent a 2\u2010week subcutaneous infusion of ANG II, with concurrent daily subcutaneous administration of the ROR\u03b3t inhibitor digoxin or vehicle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Compared with controls, ANG II\u2010infused rats exhibited elevated IL\u201017A levels in both the periphery and brain, along with increased blood pressure and sympathetic tone\u2014effects that were significantly attenuated by inhibiting ROR\u03b3t with digoxin. ANG II\u2010infused rats also displayed heightened BBB permeability, decreased expression of the BBB regulator Mfsd2a (major facilitator superfamily domain\u2010containing protein 2a), increased caveolar transcytosis, and degradation of tight junction proteins in BBB endothelial cells within the hypothalamic paraventricular nucleus, a key autonomic regulatory brain center, all of which were alleviated by digoxin. Additionally, ANG II\u2010infused rats showed marked microglial activation and elevated expression of proinflammatory cytokines within the paraventricular nucleus, both of which were mitigated by digoxin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">These findings suggest that ROR\u03b3t inhibition reduces neuroinflammation and sympathetic activation to ameliorate ANG II\u2010induced hypertension, likely by mitigating IL\u201017A\u2010induced BBB disruption and microglial activation in the paraventricular nucleus.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.040461","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:08:09Z","timestamp":1740550089000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["ROR\u03b3t Mediates Angiotensin II\u2010Induced Pressor Responses, Microglia Activation, and Neuroinflammation by Disrupting the Blood\u2013Brain Barrier in Rats"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8419-2270","authenticated-orcid":false,"given":"Yang","family":"Yu","sequence":"first","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6326-0075","authenticated-orcid":false,"given":"Baojian","family":"Xue","sequence":"additional","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tong","sequence":"additional","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4067-2157","authenticated-orcid":false,"given":"Alexander G.","family":"Bassuk","sequence":"additional","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]},{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-161X","authenticated-orcid":false,"given":"Alan K.","family":"Johnson","sequence":"additional","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]},{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4404-4059","authenticated-orcid":false,"given":"Shun\u2010Guang","family":"Wei","sequence":"additional","affiliation":[{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]},{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]},{"name":"University of Iowa Carver College of Medicine","place":["Iowa City, USA"]},{"name":"Iowa City VA Medical Center","place":["Iowa City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-012-8307-1"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.07.013"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.07.009"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.145094"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs263"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2018.01.002"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.121.18219"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.1032434"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-141978"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2019.04.011"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1651"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.032533"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1254"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.11.016"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.07.035"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1663"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07036"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1413687112"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.09.005"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.11.039"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.110.150409"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00592"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.02.028"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01743"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00914"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13324"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00049.2023"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070657"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.116.07237"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06474"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.02722"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3707"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147064"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2014.07.008"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep37977"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.10.018"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09978"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801286200"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)23835-6"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1991.261.4.H1284"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.03.010"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0274-x"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-034009"},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.11.021"},{"key":"e_1_3_1_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03782-y"},{"key":"e_1_3_1_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.03.043"},{"key":"e_1_3_1_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2020.113203"},{"key":"e_1_3_1_49_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-051116-052358"},{"key":"e_1_3_1_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-022-01187-4"},{"key":"e_1_3_1_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.197582"},{"key":"e_1_3_1_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.07.004"},{"key":"e_1_3_1_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.08.020"},{"key":"e_1_3_1_54_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.14548"},{"key":"e_1_3_1_55_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00969.2004"},{"key":"e_1_3_1_56_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000132482.95686.87"},{"key":"e_1_3_1_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.182345"},{"key":"e_1_3_1_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.109.142836"},{"key":"e_1_3_1_59_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00499.2018"},{"key":"e_1_3_1_60_2","doi-asserted-by":"publisher","DOI":"10.3791\/57648-v"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.040461","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:38:09Z","timestamp":1788874689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.040461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,4]]},"references-count":59,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,3,4]]}},"alternative-id":["10.1161\/JAHA.124.040461"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.040461","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,4]]},"assertion":[{"value":"2024-12-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e040461"}}