{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:51:18Z","timestamp":1785786678397,"version":"3.56.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL-135827"],"award-info":[{"award-number":["HL-135827"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL-119012"],"award-info":[{"award-number":["HL-119012"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL089297"],"award-info":[{"award-number":["HL089297"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL-07227"],"award-info":[{"award-number":["HL-07227"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HHSN268201000032C"],"award-info":[{"award-number":["HHSN268201000032C"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F31-HL143905"],"award-info":[{"award-number":["F31-HL143905"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["F31-HL134196"],"award-info":[{"award-number":["F31-HL134196"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["OE 688\/1-1"],"award-info":[{"award-number":["OE 688\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["20POST35180102"],"award-info":[{"award-number":["20POST35180102"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16POST29090003"],"award-info":[{"award-number":["16POST29090003"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["NHLBI-T32-HL-07227"],"award-info":[{"award-number":["NHLBI-T32-HL-07227"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18CDA34110140"],"award-info":[{"award-number":["18CDA34110140"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,7,31]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>Stimulated PKG1\u03b1 (protein kinase G-1\u03b1) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1\u03b1 oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>We tested the dependence of mTORC1 activation on PKG1\u03b1 C42 oxidation and its capacity to suppress such activation by soluble GC-1 (guanylyl cyclase 1) activation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              Cardiomyocytes expressing wild-type (WT) PKG1\u03b1 (PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              ) or cysteine-42 to serine mutation redox-dead (PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              ) were exposed to ET-1 (endothelin 1). Cells expressing PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              exhibited substantial mTORC1 activation (p70 S6K [p70 S6 kinase], 4EBP1 [elF4E binding protein-1], and Ulk1 [Unc-51-like kinase 1] phosphorylation), reduced autophagy\/autophagic flux, and abnormal protein aggregation; all were markedly reversed by PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              expression. Mice with global knock-in of PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              subjected to pressure overload (PO) also displayed markedly reduced mTORC1 activation, protein aggregation, hypertrophy, and ventricular dysfunction versus PO in PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              mice. Cardioprotection against PO was equalized between groups by co-treatment with the mTORC1 inhibitor everolimus. TSC2-S1365 phosphorylation increased in PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              more than PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              myocardium following PO. TSC2\n              <jats:sup>S1365A\/S1365A<\/jats:sup>\n              (TSC2 S1365 phospho-null, created by a serine to alanine mutation) knock-in mice lack TSC2 phosphorylation by PKG1\u03b1, and when genetically crossed with PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              mice, protection against PO-induced mTORC1 activation, cardiodepression, and mortality in PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              mice was lost. Direct stimulation of GC-1 (BAY-602770) offset disparate mTORC1 activation between PKG1\u03b1\n              <jats:sup>WT<\/jats:sup>\n              and PKG1\u03b1\n              <jats:sup>CS\/CS<\/jats:sup>\n              after PO and blocked ET-1 stimulated mTORC1 in TSC2\n              <jats:sup>S1365A<\/jats:sup>\n              -expressing myocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Oxidation of PKG1\u03b1 at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.315714","type":"journal-article","created":{"date-parts":[[2020,5,12]],"date-time":"2020-05-12T09:00:29Z","timestamp":1589274029000},"page":"522-533","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["PKG1\u03b1 Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy"],"prefix":"10.1161","volume":"127","author":[{"given":"Christian U.","family":"Oeing","sequence":"first","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taishi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"},{"name":"Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan (T.N.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Pan","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumita","family":"Mishra","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany L.","family":"Dunkerly-Eyring","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD (B.L.D.-E., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M.","family":"Kokkonen-Simon","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Lin","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangshuo","family":"Zhu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djahida","family":"Bedja","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Ik.","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Kass","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD (B.L.D.-E., D.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4970-8988","authenticated-orcid":true,"given":"Mark J.","family":"Ranek","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14332"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000749"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.01.017"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.001971"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35620"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.208314"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0895-y"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.03.035"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311147"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000057979.36322.88"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000130641.08705.45"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1144318"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2603"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0947-3"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904064116"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.037398"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80275"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.724070"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.117.004740"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.244707"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.807735"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.031"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3488"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1113\/EP086650"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/7120962"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2014.150"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.095216"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.143685"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0913860107"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.238014"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr002"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2015.01.007"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.4161\/23723548.2014.970489"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7273"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2822"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.46.32596"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152628"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C117.787358"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004363"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-012-9323-1"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/164_2016_100"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs196"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915928"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.404541"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003802"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44972"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.119.315714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:08:05Z","timestamp":1715576885000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.119.315714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,31]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,7,31]]}},"alternative-id":["10.1161\/CIRCRESAHA.119.315714"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.119.315714","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,31]]},"assertion":[{"value":"2020-05-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}