{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T17:46:32Z","timestamp":1775929592289,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,17]]},"group-title":"Molecular Biology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Type-II diabetes (DMII) and metabolic syndrome increase ventricular arrhythmia and sudden cardiac death risk.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To identify signaling mechanisms through which DMII and metabolic syndrome promote ventricular tachycardia (VT).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed ventricular programmed stimulation on leptin receptor mutant (Db\/Db) mice with DMII, high fat high sucrose (HFHS)-fed mice with metabolic syndrome, and cGMP-dependent Protein Kinase 1\u03b1 (PKG1\u03b1) leucine zipper mutant (LZM) mice, which do not have DMII or metabolic syndrome but have disrupted PKG1\u03b1 signaling.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    During ventricular programmed stimulation, Db\/Db and HFHS-fed mice displayed increased VT and T-wave alternans. Cardiomyocytes from these mice displayed early afterdepolarizations. Both models demonstrated decreased heart rate response to parasympathetic inhibition, indicating autonomic dysfunction. cGMP, which mediates cardiac parasympathetic stimulation, was reduced in LVs of Db\/Db and HFHS-fed mice. Conversely, cGMP augmentation with soluble guanylate cyclase stimulation (riociguat) or phosphodiesterase 5 inhibition (sildenafil) reduced VT inducibility. PKG1\u03b1 LZM mice had normal autonomic responsiveness, but excess VT inducibility. Db\/Db, HFHS, and LZM mice each demonstrated hyperactivated myocardial glycogen synthase kinase3\u03b2 (GSK3\u03b2). Further, GSK3\u03b2 inhibition with TWS119 abolished inducible VT in these mice. Diastolic cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    reuptake slope decreased in cardiomyocytes from all models, while GSK3\u03b2 inhibition with TWS119 reversed this effect. Phospholamban (PLB), which inhibits sarcoplasmic\/endoplasmic reticulum Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ATPase 2a-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    reuptake, was hyperactivated\/hypophosphorylated in HFHS-fed and LZM mice, and this was reversed by TWS119.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings identify cGMP reduction as driving GSK3\u03b2 hyperstimulation, calcium dyshomeostasis, and VT in DMII and metabolic syndrome. Pharmacological modulation of these pathways opposes VT pathogenesis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.12.638003","type":"posted-content","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T22:40:21Z","timestamp":1739832021000},"source":"Crossref","is-referenced-by-count":0,"title":["Myocardial cGMP-PKG1\u03b1 dysregulation contributes to VT pathogenesis in type II diabetes and metabolic syndrome"],"prefix":"10.64898","author":[{"given":"Xuehong","family":"Cao","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center"},{"name":"Tufts University School of Medicine, Boston, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yali","family":"Zhang","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center"},{"name":"Tufts University School of Medicine, Boston, 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L.","family":"Martin","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"Alissa","sequence":"additional","affiliation":[{"name":"Cardiovascular Center, Department of Medicine, Tufts Medical center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3920-2876","authenticated-orcid":false,"given":"Mossab","family":"Aljuaid","sequence":"additional","affiliation":[{"name":"Cardiovascular Center, Department of Medicine, Tufts Medical center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Ho","sequence":"additional","affiliation":[{"name":"Tufts University School of Medicine, 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