{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:12:55Z","timestamp":1792671175585,"version":"4.5.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T00:00:00Z","timestamp":1701993600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,12,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Nitric oxide (NO) has been identified as a signaling molecule generated during \u03b2-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release via\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosylation of CaMKII\u03b4 (Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosylation of CaMKII\u03b4 at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling and arrhythmogenesis before and during \u03b2-adrenergic receptor stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We measured Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -handling in isolated cardiomyocytes from C57BL\/6J wild-type (WT) mice and mice lacking CaMKII\u03b4 expression (CaMKII\u03b4-KO) or with deletion of the\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosylation site on CaMKII\u03b4 at cysteine-273 or cysteine-290 (CaMKII\u03b4-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors,\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosoglutathione (GSNO; 150 \u03bcM), sodium nitroprusside (200 \u03bcM), and \u03b2-adrenergic agonist isoproterenol (100 nmol\/L).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Both WT and CaMKII\u03b4-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transient response as well as increased Ca\n                      <jats:sup>2+<\/jats:sup>\n                      spark frequency. However, the increase in Ca\n                      <jats:sup>2+<\/jats:sup>\n                      spark frequency was significantly attenuated in CaMKII\u03b4-KO cardiomyocytes. The protection from isoproterenol-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKII\u03b4-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKII\u03b4-C273S but was apparent in CaMKII\u03b4-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKII\u03b4-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      We conclude that prior\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosylation of CaMKII\u03b4 at cysteine-273 can limit subsequent \u03b2-adrenergic receptor\u2013induced arrhythmias, but that\n                      <jats:italic>S<\/jats:italic>\n                      -nitrosylation at cysteine-290 might worsen or sustain \u03b2-adrenergic receptor\u2013induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.323571","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T05:00:20Z","timestamp":1699938020000},"page":"1040-1055","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Nitric Oxide Modulates Ca\n                    <sup>2+<\/sup>\n                    Leak and Arrhythmias via S-Nitrosylation of CaMKII"],"prefix":"10.1161","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7920-9266","authenticated-orcid":true,"given":"Amelia S.","family":"Power","sequence":"first","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."},{"name":"Department of Physiology, University of Auckland, New Zealand (A.S.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther U.","family":"Asamudo","sequence":"additional","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."},{"name":"Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke P.I.","family":"Worthington","sequence":"additional","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chidera C.","family":"Alim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel E.","family":"Parackal","sequence":"additional","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3304-9524","authenticated-orcid":true,"given":"Rachel S.","family":"Wallace","sequence":"additional","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5238-928X","authenticated-orcid":true,"given":"Obialunanma V.","family":"Ebenebe","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (O.V.E., M.J.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Heller Brown","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, San Diego, La Jolla (J.H.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-5962","authenticated-orcid":true,"given":"Mark J.","family":"Kohr","sequence":"additional","affiliation":[{"name":"Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (O.V.E., M.J.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":true,"given":"Donald M.","family":"Bers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R.","family":"Erickson","sequence":"additional","affiliation":[{"name":"Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.055384"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)33279-4"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20792-5"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.06.007"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.07.019"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.4.C1371"},{"key":"e_1_3_3_8_2","first-page":"801","article-title":"Nitroglycerin--the first one hundred years: new facts about an old drug.","volume":"31","author":"Parratt JR","year":"1979","unstructured":"Parratt, JR. 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