{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:20:46Z","timestamp":1793413246312,"version":"4.5.0"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale:<\/jats:title>\n                    <jats:p>\n                      Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calmodulin-dependent kinase II) activation may occur in diabetes mellitus and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1)\n                      <jats:italic>O<\/jats:italic>\n                      -linked attachment of N-acetylglucosamine (\n                      <jats:italic>O<\/jats:italic>\n                      -GlcNAc) at S280 leading to arrhythmia and (2) a reactive oxygen species (ROS)\u2013mediated oxidation of CaMKII that can increase postinfarction mortality.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To test whether high extracellular glucose (Hi-Glu) promotes ventricular myocyte ROS generation and the role played by CaMKII.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      We tested how extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using DCF (2\u2032,7\u2032-dichlorodihydrofluorescein diacetate) and genetically targeted Grx-roGFP2 redox sensors. Hi-Glu (30 mmol\/L) significantly increased the rate of ROS generation\u2014an effect prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from either global or cardiac-specific CaMKII\u03b4 KO (knockout) mice. CaMKII KO or inhibition also prevented Hi-Glu\u2013induced sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release events (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sparks). Thus, CaMKII activation is required for Hi-Glu\u2013induced ROS generation and sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak in cardiomyocytes. To test the involvement of\n                      <jats:italic>O<\/jats:italic>\n                      -GlcNAc\u2013CaMKII pathway, we inhibited GlcNAcylation removal by Thiamet G (ThmG), which mimicked the Hi-Glu\u2013induced ROS production. Conversely, inhibition of GlcNAcylation (OSMI-1 [(\u03b1R)-\u03b1-[[(1,2-dihydro-2-oxo-6-quinolinyl)sulfonyl]amino]-N-(2-furanylmethyl)-2-methoxy-N-(2-thienylmethyl)-benzeneacetamide]) prevented ROS induction in response to either Hi-Glu or ThmG. Moreover, in a CRSPR-based knock-in mouse in which the functional GlcNAcylation site on CaMKII\u03b4 was ablated (S280A), neither Hi-Glu nor ThmG induced myocyte ROS generation. So CaMKII\u03b4-S280 is required for the Hi-Glu\u2013induced (and GlcNAc dependent) ROS production. To identify the ROS source(s), we used different inhibitors of NOX (NADPH oxidase) 2 (Gp91ds-tat peptide), NOX4 (GKT137831), mitochondrial ROS (MitoTempo), and NOS (NO synthase) pathway inhibitors (L-NAME, L-NIO, and L-NPA). Only NOX2 inhibition or KO prevented Hi-Glu\/ThmG\u2013induced ROS generation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Diabetic hyperglycemia induces acute cardiac myocyte ROS production by NOX2 that requires\n                      <jats:italic>O<\/jats:italic>\n                      -GlcNAcylation of CaMKII\u03b4 at S280. This novel ROS induction may exacerbate pathological consequences of diabetic hyperglycemia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.119.316288","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T14:33:03Z","timestamp":1584541983000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":154,"title":["Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via\n                    <i>O<\/i>\n                    -linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes"],"prefix":"10.1161","volume":"126","author":[{"given":"Shan","family":"Lu","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis School of Medicine (S.L., Z.L., J.B., D.M.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhandi","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis School of Medicine (S.L., Z.L., J.B., D.M.B.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renji Hospital School of Medicine, Jiaotong University, Shanghai, China (X.L.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00f6rthe M.","family":"Katschinski","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Physiology, University Medical Centre G\u00f6ttingen, Germany (D.M.K.)"},{"name":"German Center for Cardiovascular Research, Partner Site, G\u00f6ttingen (D.M.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mercola","sequence":"additional","affiliation":[{"name":"Stanford Cardiovascular Institute and Department of Medicine, Stanford University, CA (M.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine (J.C.), University of California San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Heller Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmacology (J.H.B.), University of California San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati, Cincinnati Children\u2019s Hospital Medical Center, OH (J.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology, University of California, Davis School of 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