Probucol prevents atrial ion channel remodeling in an alloxan-induced diabetes rabbit model.

Huaying Fu,Jian Li,Lijun Cheng,Gary Tse,Wansong Yang,Changle Liu,Guangping Li,Tong Liu,Jichao Zhao

doi:10.18632/oncotarget.13339

Abstract

Diabetes mellitus (DM) increases the risk of developing atrial fibrillation (AF), but the molecular mechanisms of diabetes-induced atrial remodeling processes have not been fully characterized. The aim of this study was to examine the mechanisms underlying atrial ion channel remodeling in alloxan-induced diabetes model in rabbits. A total of 40 Japanese rabbits were randomly assigned to a control group (C), alloxan-induced diabetic group (DM), probucol-treated control group (Control-P), and probucol-treated diabetic group (DM-P). Using whole-cell voltage-clamp techniques, ICa,L, INa and action potential durations (APDs) were measured in cardiomyocytes isolated from the left atria in the four groups, respectively. In the DM group, increased Ica,L and decreased INa currents were reflected in prolonged APD90 and APD50 values. These changes were reversed in the DM-P group. In conclusion, probucol cured AF by alleviating the ion channel remodeling of atrial myocytes in the setting of diabetes and the promising therapeutic potential of anti-oxidative compounds in the treatment of AF warrants further study.

Highlights

Nowadays, atrial fibrillation (AF) is the most common arrhythmic condition encountered in clinical practice, producing significant morbidity and mortality via the development of various concurrent diseases and consequences, such as strokes and myocardial infarction [1]
We discovered that diabetes mellitus (DM) led to increased levels of cholesterol, triglyceride and low density lipoprotein cholesterin (LDL-c), as well as higher MPO, and lower superoxide dismutase (SOD) and CAT concentrations compared to control (P < 0.05), but not significance in renal function (BUN and creatinine values) (P > 0.05)
The probucol treatment reversed the rise in the lipid peroxidation product, malondialdehyde (MDA) in the DM group (P < 0.05)

Summary

Introduction

Atrial fibrillation (AF) is the most common arrhythmic condition encountered in clinical practice, producing significant morbidity and mortality via the development of various concurrent diseases and consequences, such as strokes and myocardial infarction [1]. As one independent risk factor of AF, diabetes mellitus (DM) is a clinical condition that is becoming increasingly prevalent, in part due to a rising level of obesity, and has been shown to increase atrial arrhythmogenicity through structural and electrophysiological remodeling [2,3,4]. In an alloxan-induced diabetic rabbit model, our group had previously demonstrated that hyperglycemic conditions lead to increased interstitial fibrosis and higher likelihood of AF development[7], as well as reduction of the Na+ current (INa) and increasement of the Ca2+ current (ICaL) in the atria [8]. Reduction of INa current due to reduced mRNA and protein levels was observed [12]. Together, these changes can lead to both triggered and re-entrant arrhythmogenesis

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