Abstract
Increased atrial oxidative stress has an important role in inducing and maintaining atrial fibrillation (AF), and the activation of the small GTPase Rac1 contributes to the oxidative stress. We investigated the relationship of Rac1, atrial endothelial thromboprotective markers and AF inducibility and if simvastatin has a potential beneficial effect on a myocardial infarction (MI)-induced heart failure (HF) rat model. Rats were randomized into three groups (shams, MI group and simvastatin treatment group) and underwent echocardiography, AF induction studies and left atrial (LA) fibrosis analysis. Atrial Rac 1, sodium calcium exchanger (INCX), sarcoplasmic reticulum calcium ATPase (SERCA), endothelial nitric oxide synthase (eNOS) and induced nitric oxide synthase (iNOS) were measured. AF inducibility, AF duration and LA fibrosis were significantly higher in the MI group (p < 0.001 vs. sham), which were significantly reduced by simvastatin (p < 0.05 vs. MI). The reduced expressions of atrial eNOS, SERCA, thrombomodulin, tissue factor pathway inhibitor and tissue plasminogen activator in the MI group were significantly improved by simvastatin. Furthermore, the increased expression of atrial iNOS, INCX and Rac1 activity were significantly decreased by the simvastatin. Oxidative stress, endothelial dysfunction and thrombogenicity are associated with the promotion of AF in a rat model of ischemic HF. These were associated with increased Rac1 activity, and simvastatin treatment prevents these changes.
Highlights
Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and is a potent risk factor for ischemic stroke [1]
Immunohistochemical staining for induced nitric oxide synthase (iNOS) revealed little activity in the sham group, but myocardial iNOS activity was higher in the myocardial infarction (MI) group
Group was lower than the sham, and endothelial nitric oxide synthase (eNOS) expression in the MI + simvastatin group was higher than the MI group; and (B) iNOS expression in the MI
Summary
Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia and is a potent risk factor for ischemic stroke [1]. Some studies have suggested that statins block atrial remodeling induced by substances such as NO and reactive oxygen species [9,10] In addition to their indirect antiarrhythmic effects, statins may exhibit direct antiarrhythmic effects by modulating the fatty acid composition and physiochemical properties of cell membranes, with resultant alterations in transmembrane ion channel properties [10,11]. Sarr et al [15], hydrophilic pravastatin exhibited the lowest association with the lipid monolayer, and lipophilic simvastatin showed a strong membrane elution ability, which can be explained by the hydrophobicity of the statin molecule [16] These findings suggest that the difference of membrane permeability according to the lipophilicity might explain the impact of statin on the ion channel in the cell membrane. The changes in Rac 1, the inducibility of AF and atrial endothelial thromboprotective markers with or without statin in a rat model of ischemic HF model
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