{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T01:42:25Z","timestamp":1792374145430,"version":"4.4.0"},"reference-count":77,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2025,12,23]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Nitric oxide (NO), generated by the endothelial NO synthase (eNOS), regulates vascular tone and endothelial homeostasis to counteract vascular inflammation. Most eNOS is localized at the cell membrane or in the Golgi apparatus, but the enzyme is also present in the endothelial cell nucleus. Here, we assessed the relevance of nuclear eNOS and NO signaling for endothelial cell function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>eNOS loss-of-function approaches were combined with confocal microscopy and biochemical, histological, and multiomics analyses. The pathophysiological relevance of the findings was assessed in murine models of atherogenesis (hypercholesterolemia and partial carotid ligation) as well as in samples from patients with atherosclerosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      eNOS was present in the nucleus of unstimulated human and murine endothelial cells (in vitro and ex vivo) and stimulation with VEGF (vascular endothelial growth factor) enhanced its nuclear localization. Coimmunoprecipitation studies coupled with proteomics revealed the association of nuclear eNOS with 81 proteins involved in RNA binding and processing. Among the latter was ADAR1 (double-stranded RNA-specific adenosine deaminase), an enzyme involved in editing double-stranded RNA via the deamination of A to I. ADAR1 was\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      -nitrosated in human endothelial cells, and the knockdown of eNOS resulted in altered ADAR1-mediated A-to-I editing and an increase in double-stranded RNA. The latter phenomenon elicited aggregation of MAVS (mitochondrial antiviral signaling protein), activation of the type I IFN (interferon) signaling pathway and a marked downregulation of cell cycle\u2013related genes. ADAR1 depletion elicited similar effects on the activation of type I IFN signaling. As a result, growth factor\u2013stimulated cell proliferation was abrogated, and basal as well as stimulated cell death were increased in endothelial cells lacking eNOS. Endothelial dysfunction in mice as well as in subjects with atherosclerosis was accompanied by accumulation of double-stranded RNA and activation of type I IFN signaling. Preserving NO bioavailability in vivo (Tyr657Phe eNOS mice) prevented these effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings uncovered a novel mechanism linking nuclear eNOS-derived NO with the activity of ADAR1 to maintain vascular homeostasis. Reduced NO bioavailability results in previously unrecognized activation of a type I IFN response in the endothelium, which contributes to atherogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074889","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T09:22:13Z","timestamp":1761729733000},"page":"1781-1799","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Nuclear eNOS Interacts With and\n                    <i>S<\/i>\n                    -Nitrosates ADAR1 to Modulate Type I Interferon Signaling and Endothelial Function"],"prefix":"10.1161","volume":"152","author":[{"given":"Xiaozhu","family":"Zhou","sequence":"first","affiliation":[{"name":"Institute for Vascular Signaling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany (X.Z., B.G., F.D.L., I.F., 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