Reactive oxygen species mediated oxidative stress links diabetes and atrial fibrillation

Abstract

Diabetes is an independent risk factor for atrial fibrillation (AF); however, the underlying mechanism linking diabetes and AF remains to be clarified. The present study aimed to explore the molecular mechanism of increased reactive oxygen species (ROS) production in AF and the ROS-mediated downstream events in diabetes. Firstly, the atrial fibroblasts were isolated from the left atrium of rabbits using enzyme digestion and differential adhesion. Then, the isolated cells were identified by morphology analysis under a microscope, collagen distribution using Masson trichrome staining and vimentin by immunofluorescence. Following this, the collected atrial fibroblasts were randomly divided into 7 groups and administered with high glucose (25 mM glucose), H2O2 stimulation (100 nmol/l), glucose + apocynin (100 µg/ml), H2O2 + apocynin, glucose + H2O2, and a combination of glucose, apocynin and H2O2, as well as the negative control (NC). An MTS assay was performed to investigate cell proliferation following the different treatments, and western blotting was conducted to explore the expression of several proteins including NAD(P)H oxidative (NOX) subunits, key factors involved in mitogen-activated protein kinase (MAPK) signaling pathways and matrix metalloproteinases (MMPs). The atrial fibroblasts were spindle-shaped with one or more protuberances. Vimentin was positively expressed in collected cells under confocal laser scanning microscopy. This result indicated that the atrial fibroblasts were successfully prepared. High glucose and H2O2 stimulation significantly increased the proliferation of atrial fibroblasts and apocynin markedly attenuated the promoting effects on cell proliferation induced by high glucose and H2O2 treatment (P<0.05). Additionally, high glucose and H2O2 stimulation increased the expression of Rac1, phospho(p)-c-Jun N-terminal kinase 1, p38, p-p38 and MMP9, which was markedly decreased by the addition of apocynin (P<0.05). The mechanism associated with diabetes and AF may be attributed to oxidative stress (ROS production) derived from NOX activity, and then induced activation of the MAPK signaling pathways and MMP9 expression.

Cardio metabolic risk factors for atrial fibrillation in type 2 diabetes mellitus: Focus on hypertension, metabolic syndrome and obesity

“…Atrial dilatation is also enhanced by the proliferation of atrial fibroblasts. Both conditions lead to structural and electrical remodeling of the left atrium and explain the development of AF in T2DM (1,13,14). The contribution of oxidative stress might also be determined by additional exposure to exogenous sources of ROS, as well as the reduced capacity of antioxidant defense systems to scavenge these molecules in the elderly since their efficiency is age-dependent (15,16).…”

The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

“…Thus, elevated NO likely represents increased oxidative stress in a HG environment. Further supporting a contribution for oxidative stress to fibroblast phenotype in diabetes, the free radical hydrogen peroxide (H 2 O 2 ) can induce proliferation in rabbit atrial fibroblasts, and oxidative stress contributes to HG-induced proliferation in these cells, since the reduced nicotinamide adenine dinucleotide phosphate inhibitor, apocynin, could inhibit proliferation [70]. HG induced p38 activation, which was prevented by apocynin inhibition of oxidative stress.…”

Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity

“…Genetically obese models include ob/ob , db/db and Zucker diabetic fatty (ZDF) hyperglycemic rodents, while obesity can also be induced by high fat diet (HFD) or high-sucrose diet ( King and Bowe, 2016 ). Although larger animal models have been studied more recently ( Xie et al, 2013 ; Zhang et al, 2017 ; Liang et al, 2018 ; Yang et al, 2018 ), most research investigating diabetes-related ventricular arrhythmias to date has been performed on rodents and remains limited. Conversely, functional alterations of Ca 2+ handling proteins and EC coupling in HF have been extensively researched over several decades, in both small and large animal models as well as failing human cardiomyocytes ( Hasenfuss et al, 1994 ; Studer et al, 1994 ; Schmidt et al, 1999 ; Louch et al, 2004 ; Sossalla et al, 2010 ; Crossman et al, 2011 ; Ottolia et al, 2013 ; Zima et al, 2014 ; Gorski et al, 2015 ; Høydal et al, 2018 ).…”