{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:03:50Z","timestamp":1789715030890,"version":"4.0.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Vascular remodeling, a pathological hallmark of hypertensive target\u2010organ damage, is critically modulated by autophagy. Given the emerging role of TWEAK (tumor necrosis factor\u2013like weak inducer of apoptosis)\/TWEAK receptor (TWEAKR) signaling in cardiovascular pathogenesis, this study investigates the relationship between TWEAK\/TWEAKR and autophagy in hypertension\u2010associated vascular remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Peripheral blood TWEAK levels were measured in patients with hypertension and spontaneously hypertensive rats. To elucidate the role of TWEAKR in autophagy and vascular remodeling, lentivirus\u2010mediated knockdown of TWEAKR was performed. A multiple strategy integrating western blot, reverse transcription polymerase chain reaction, coimmunoprecipitation, liquid chromatography\u2013mass spectrometry, RNA sequencing, immunohistochemistry and immunofluorescence staining, and transmission electron microscopy was used. Experimental validation was conducted in\u00a0vitro using rat aortic vascular smooth muscle cells and in\u00a0vivo using spontaneously hypertensive rats and their normotensive controls, Wistar\u2013Kyoto rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Serum TWEAK levels were unchanged in patients with hypertension and spontaneously hypertensive rats compared with controls, whereas TWEAKR expression was elevated. TWEAKR knockdown attenuated vascular remodeling and suppressed abnormal autophagy, independent of blood pressure or heart rate. Specifically, TWEAKR knockdown inhibited angiotensin II\u2013induced autophagy, while TWEAKR overexpression enhanced this process. Furthermore, TWEAKR knockdown suppressed excessive proliferation, migration, and phenotypic switch of rat aortic vascular smooth muscle cells. Mechanistically, TWEAKR regulated autophagy by inhibiting TRIM21 (tripartite motif containing 21) expression via the ERK1\/2 (extracellular signal\u2010regulated kinase 1\/2) pathway. Reduced TRIM21 decreased eIF4A3 (eukaryotic translation initiation factor 4A3) ubiquitination, promoting its nuclear translocation and inducing autophagy, thereby exacerbating vascular remodeling. TRIM21 interacted with eIF4A3 via its coiled\u2010coil domain, primarily catalyzing K63\u2010linked polyubiquitination. Notably, vascular remodeling was attenuated by TWEAKR knockdown but not by dual knockdown of TWEAKR and TRIM21.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">TWEAKR regulates TRIM21 levels through the ERK1\/2 pathway, modulating eIF4A3 subcellular localization and autophagy, thereby influencing hypertension\u2010associated vascular remodeling. These findings highlight TWEAKR as a potential therapeutic target for hypertension\u2010induced vascular pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.040733","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:10:28Z","timestamp":1778757028000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["TWEAK Receptor Promotes Vascular Remodeling in Hypertension by Activating Autophagy"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8076-3064","authenticated-orcid":false,"given":"Qingsu","family":"Lan","sequence":"first","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Department of Cardiology","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7641-0934","authenticated-orcid":false,"given":"Wenqiang","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Department of Cardiology","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Department of Cardiology","place":["Jinan, China"]},{"name":"Qilu Hospital of Shandong University","place":["Jinan, China"]},{"name":"Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University","place":["Qingdao, 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