Molecular basis of ventricular arrhythmogenicity in a Pgc-1α deficient murine model

Abstract

Mitochondrial dysfunction underlying metabolic disorders such as obesity and diabetes mellitus is strongly associated with cardiac arrhythmias. Murine Pgc-1α −/− hearts replicate disrupted mitochondrial function and model the associated pro-arrhythmic electrophysiological abnormalities. Quantitative PCR, western blotting and histological analysis were used to investigate the molecular basis of the electrophysiological changes associated with mitochondrial dysfunction. qPCR analysis implicated downregulation of genes related to Na + -K + ATPase activity (Atp1b1), surface Ca 2+ entry (Cacna1c), action potential repolarisation (Kcnn1), autonomic function (Adra1d, Adcy4, Pde4d, Prkar2a), and morphological properties (Myh6, Tbx3) in murine Pgc-1α −/− ventricles. Western blotting revealed reduced Na V 1.5 but normal Cx43 expression. Histological analysis revealed increased tissue fibrosis in the Pgc-1α −/− ventricles. These present findings identify altered transcription amongst a strategically selected set of genes established as encoding proteins involved in cardiac electrophysiological activation and therefore potentially involved in alterations in ventricular activation and Ca 2+ homeostasis in arrhythmic substrate associated with Pgc-1α deficiency. They complement and complete previous studies examining such expression characteristics in the atria and ventricles of Pgc-1 deficient murine hearts.

Exploring early DNA methylation alterations in type 1 diabetes: implications of glycemic control

“…GNAS is important for β-cell insulin secretion, with reduced expression observed in pancreatic islets from individuals with type 2 diabetes ( 60 ) and in urine from individuals with diabetes ( 61 ). Downregulation of ADCY4 has been associated to impaired mitochondrial function in murine hearts ( 62 ), while hyperglycemia-induced cardiac hypertrophy and apoptosis act through endoplasmic reticulum stress-JNK3 signaling pathway ( 63 ). JNK3 has been shown to play a critical role in diabetes-induced atrial fibrillation in mice ( 64 ).…”

Cardiac ion channel expression in the equine model ‐ In‐silico prediction utilising RNA sequencing data from mixed tissue samples

“…Following membrane depolarisation, outward membrane current resulting from K + channel opening drives action potential repolarisation, controlling action potential duration whose prolongation is associated with arrhythmic tendency. These include transient outward (I to ) and delayed rectifier currents (I Kr , I Ks ) (Huang, 2017 ; Jeevaratnam et al, 2018 ; Saadeh et al, 2021 ). It is known that there is significant species‐dependent variety of K + channels.…”

Anti‐malarial drugs: Mechanisms underlying their proarrhythmic effects

“…These induce fibroblast proliferation, differentiation into myofibroblasts and the production of extracellular matrix components (Biernacka & Frangogiannis, 2011 ). Both clinical and experimental studies strongly associate fibrosis with atrial and ventricular arrhythmias (de Bakker et al, 1990 ; Hassink et al, 2003 ; Saadeh et al, 2021 ). For example, isolated Langendorff‐perfused human hearts with extensive infarction or dilated cardiomyopathy demonstrated increased vulnerability to triggering of ventricular tachycardia due to cardiac fibrosis facilitating re‐entry mechanisms (de Bakker et al, 1990 ; Wu et al, 1998 ).…”