Products Cited in Publications Worldwide Myocardial cGMP-PKG1alpha dysregulation contributes to VT pathogenesis in type II diabetes and metabolic syndrome

Myocardial cGMP-PKG1alpha dysregulation contributes to VT pathogenesis in type II diabetes and metabolic syndrome

Cao, Xuehong; Zhang, Yali; Tripp, Audrey Elisabeth; Steinhauer, Rachael; Liu, Peiwen; Aronovitz, Mark; Martin, Gregory L; Wang, Bo; Alissa, Abdullah; AlJuaid, Mossab

DOI:

Abstract

Background: Type-II diabetes (DMII) and metabolic syndrome increase ventricular arrhythmia and sudden cardiac death risk. Objectives: To identify signaling mechanisms through which DMII and metabolic syndrome promote ventricular tachycardia (VT). Methods: 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 1α (PKG1α) leucine zipper mutant (LZM) mice, which do not have DMII or metabolic syndrome but have disrupted PKG1α signaling. Results: 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. PKG1α LZM mice had normal autonomic responsiveness, but excess VT inducibility. Db/Db, HFHS, and LZM mice each demonstrated hyperactivated myocardial glycogen synthase kinase3β (GSK3β). Further, GSK3β inhibition with TWS119 abolished inducible VT in these mice. Diastolic cytosolic Ca2+ reuptake slope decreased in cardiomyocytes from all models, while GSK3β inhibition with TWS119 reversed this effect. Phospholamban (PLB), which inhibits sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a-mediated Ca2+ reuptake, was hyperactivated/hypophosphorylated in HFHS-fed and LZM mice, and this was reversed by TWS119. Conclusions: These findings identify cGMP reduction as driving GSK3β hyperstimulation, calcium dyshomeostasis, and VT in DMII and metabolic syndrome. Pharmacological modulation of these pathways opposes VT pathogenesis.

Keywords

Ventricular tachycardia ; Diabetes ; Arrhythmia ; cGMP ; GSK3β ; Autonomic dysfunction

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Riociguat

A255332625115-55-195%

Riociguat

60.0/250mg

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