{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:41:19Z","timestamp":1788795679341,"version":"build-2803163510"},"reference-count":46,"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":[[2024,3,29]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Vascular large conductance Ca\n              <jats:sup>2+<\/jats:sup>\n              -activated K\n              <jats:sup>+<\/jats:sup>\n              (BK) channel, composed of the \u03b1-subunit (BK-\u03b1) and the \u03b21-subunit (BK-\u03b21), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-\u03b1 mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-\u03b1 subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-\u03b21 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-\u03b1\/BK-\u03b21 channel current density. Additionally,\n              <jats:italic>Sorbs2<\/jats:italic>\n              is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of\n              <jats:italic>Sorbs2<\/jats:italic>\n              and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that\n              <jats:italic>Sorbs2<\/jats:italic>\n              knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca\n              <jats:sup>2+<\/jats:sup>\n              -sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db\/db type 2 diabetic mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of\n              <jats:italic>Sorbs2<\/jats:italic>\n              manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.123.323538","type":"journal-article","created":{"date-parts":[[2024,2,16]],"date-time":"2024-02-16T10:00:29Z","timestamp":1708077629000},"page":"858-871","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Sorbs2 Deficiency and Vascular BK Channelopathy in Diabetes"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1726-0365","authenticated-orcid":true,"given":"Xiaojing","family":"Sun","sequence":"first","affiliation":[{"name":"The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, 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