Myocardial PKG1α dysregulation contributes to ventricular tachycardia pathogenesis in type 2 diabetes and metabolic syndrome
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 Ca2+ reuptake was delayed in cardiomyocytes (CMs) from all 3 models, reflected by increased time constant of cytoplasmic Ca2+ decline, tau. TWS119 reversed this effect. Phospholamban, which when unphosphorylated inhibits sarcoplasmic/endoplasmic…
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