Work

Myocardial PKG1α dysregulation contributes to ventricular tachycardia pathogenesis in type 2 diabetes and metabolic syndrome

Year: 2025

Type: article

Abstract: Background Type 2 diabetes mellitus (DMII) and metabolic syndrome (MBS) increase ventricular arrhythmia and sudden cardiac death risk. Objective This study aimed to identify mechanisms through which DMII and MBS promote ventricular tachycardia (VT). Methods We performed programmed ventricular stimulation on leptin receptor mutant (Db/Db) mice with DMII; high-fat, high-sucrose (HFHS) diet–fed mice with MBS; and cyclic guanosine monophosphate (cGMP)-dependent protein kinase 1 alpha (PKG1α) leucine zipper mutant (LZM) mice, which have neither DMII nor MBS but have disrupted PKG1α signaling. Results Programmed ventricular stimulation induced VT in Db/Db and HFHS diet–fed mice. Both models demonstrated autonomic dysfunction and decreased cGMP owing to decreased cardiac parasympathetic responsiveness. Conversely, cGMP augmentation with soluble guanylate cyclase stimulation (riociguat) or phosphodiesterase 5 inhibition (sildenafil) reduced VT inducibility. PKG1α LZM mice had normal autonomic responsiveness, but excess VT. Left ventricular tissue from HFHS diet–fed and LZM mice demonstrated hyperactivated glycogen synthase kinase-3 beta (GSK3β). GSK3β inhibition with TWS119 abolished inducible VT in all 3 models. Sarcoplasmic reticulum Ca 2+ reuptake was delayed in cardiomyocytes (CMs) from all 3 models, reflected by increased time constant of cytoplasmic Ca 2+ decline, tau. TWS119 reversed this effect. Phospholamban, which when unphosphorylated inhibits sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a–mediated Ca 2+ reuptake from the cytosol, was hypophosphorylated in HFHS diet–fed and LZM mice, which was reversed by TWS119. CMs from HFHS diet–fed mice displayed increased frequency of early afterdepolarizations, further supporting Ca 2+ dyshomeostasis. cGMP augmentation with riociguat/sildenafil prevented afterdepolarizations in HFHS CMs. Conclusion In DMII and MBS, reduced PKG1α signaling drives GSK3β hyperstimulation, calcium dyshomeostasis, and VT. Pharmacologic modulation of these pathways opposes VT pathogenesis.

Source: Heart Rhythm

DOI: 10.1016/j.hrthm.2025.08.032