Research On The Ion And Molecular Mechanism Of Atrial Electrical And Structural Remodeling During Aging And Atrial Fibrillation

Objective: This study was to investigate whether or not the dysfunction of atrialrepolarization and abnormality of the intracellular Ca2+handling protein was augmentedwith aging; to investigate the correlation between the change in the expression of atrialcalpains and electrical, molecular, and structural remodeling during aging and AF; toinvestigate whether abnormal expressions of matrix metalloproteinase (MMP)-9/tissueinhibitors of MMPs (TIMP)-1and BCL-2/BAX are correlated with the characteristicaccelerated fibrosis and apoptosis during aging and AF; to investigate whether or not theaberrant expression of microRNA-1, microRNA-21, microRNA-29and microRNA-133show a correlation with structural remodeling during aging and AF, and demonstrate thatthese miRNAs, acting singly or in combination, may be responsible for modulating thetransition from adaption to pathological atrial remodelling. Methods: Four groups ofdogs were studied; younger adult and aged dogs in sinus rhythm (SR) and atrialfibrillation (AF) induced by rapid atrial pacing. We used whole cell patch clamprecording techniques to measure L-type Ca2+current (ICa-L) in cells dispersed from theleft atria. The mRNA and protein expressions of the target proteins in the left atrium weremeasured by quantitative RT-PCR and Western blot analysis. The expressions of thetarget microRNAs were measured by Quantitative Real-Time Polymerase Chain Reaction(qRT-PCR). Pathohistological and ultrastructural changes were tested by light andelectron microscopy. Apoptosis indices of myocytes were detected by TUNEL. Results:In SR groups, atrial cells of the old dogs had longer action potential (AP) duration to90%repolarization (APD90), lower AP plateau potential, and peak ICa-Lcurrent densities(all P＜0.05). In both ages, AF led to a higher maximum diastolic potential, a increase ofAP amplitude, decreases of APD90, AP plateau potential and peak ICa-Ldensities (all P＜ 0.05). Compared to the adult group, the mRNA and protein expressions of LVDCCa1cwere decreased in the aged group, whereas the expressions of calcium adenosinetriphosphatase were increased; the mRNA and protein expressions of MMP-9and BAXand those of TIMP-1and BCL-2exhibited a significant increase and a down-regulationpattern, respectively, in the aged groups compared with the adult groups; compared to theadult group, the expressions of miR-21,29was significantly increased, whereas theexpressions of miR-1,133showed obviously down-regulation tendence in the aged group(all P＜0.05). Compared to SR group, expressions of LVDCCa1c and Ca2+handlingprotein except for phospholamban were significantly decreased in both age groups withAF; the mRNA and protein expressions of calpain1were increased in both the adult andold groups with AF; compared with the control groups, the adult and old groups with AFexhibited significantly increased mRNA and protein expressions of MMP-9and BAXand down-regulated expressions of TIMP-1and BCL-2; compared to the aged group, theexpressions of miR-1,21,29was significantly increased in the old group in AF, incontrast, the expressions of miR-133showed obviously down-regulation tendence (all P＜0.05). Samples of atrial tissue showed abnormal pathohistological and ultrastructuralchanges like accelerated fibrosis and apoptosis with aging and in AF (all P＜0.05).Conclusions: These aging-induced electrophysiological and molecular changes showedthat general pathophysiological adaptations might provide a substrate conducive to AF.Age-related alterations in atrial tissues can be attributed to increased expressions ofcalpain1. MMP-9/TIMP-1and BCL-2/BAX hold potential for use as substratesconducive to AF, and their abnormal expressions play a major role in atrial structuralremodelling. These multiple aberrantly expressed miRNAs may be responsible formodulating the transition from adaption to pathological atrial remodelling with agingand/or in AF.