Prevention of Atrial Fibrillation by Using Sarcoplasmic Reticulum Calcium ATPase Pump Overexpression in a Rabbit Model of Rapid Atrial Pacing

Abstract

BackgroundRecent research suggests that abnormal Ca2+ handling plays a role in the occurrence and maintenance of atrial fibrillation (AF). Therefore, Ca2+ release and ingestion depend on properties of the ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ATPase2a (SERCA2a). This study aimed to detect whether SERCA2a gene overexpression has a preventive effect on atrial fibrillation caused by rapid pacing right atrium.Material/MethodsForty-eight New Zealand white rabbits were randomly divided into a control group, AF group, AAV9/GFP group, and AAV9/SERCA2a group. The right atrium was rapidly paced at 600 beats/min for 30 days after an intraperitoneal injection of an adeno-associated virus expressing the SERCA2a gene and GFP. The AF induction rate and the effective refraction period (ERP) were measured after 0, 4, 8, 12, and 24 h of pacing. Western blot analysis was used to test for the expression of SERCA2a. Changes in atrial tissue structure were observed by H&E staining and electron microscopy.ResultsThe AF induction rate was higher in the AF groups than in the AAV9/SERCA2a group at different time points of pacing. After 12 h of pacing, ERP was significantly prolonged in the AAV9/SERCA2a group compared to the AF and AAV9/GFP groups (p<0.05). SERCA2a protein expression was significantly lower in the AF and AAV9/GFP groups compared to the control group (p<0.05), while expression was significantly higher in the AAV9/SERCA2a group than in the AF and AAV9/GFP groups (p<0.05). The myocardial structure of the AAV9/SERCA2a group was significantly improved compared with the AF group, indicating that SERCA2a overexpression relieved the structural remodeling of atrial fibrillation.ConclusionsSERCA2a overexpression is capable of suppressing ERP shortening and AF induced by rapid pacing atrium. SERCA2a gene therapy is expected to be a new anti-atrial fibrillation strategy.

Elevated β1-Adrenergic Receptor Autoantibody Levels Increase Atrial Fibrillation Susceptibility by Promoting Atrial Fibrosis

“…AERP and AF inducibility were measured as described in our previous study (Wang et al, 2017). AERP was conducted with a programmed train of eight basic stimuli (S1-S1 = 260 ms) followed by one extra stimulus (S2) with an initial pacing length of 200 ms and 5 ms decrements until S2 failed to capture the depolarization.…”

“…The atrial tissue was sliced into 5 µmthick cross-sections to visualize the cell structure. The sections were deparaffinized and subjected to hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and picrosirius red staining for assessment of basic tissue structure and detection of fibrosis following the methods of our previous study (Wang et al, 2017). Digital photographs were taken under a Leica microscope (DM2500, Wetzlar, Germany).…”

“…Western blot analysis was performed to detect the expression levels of transforming growth factor-β1 (TGF-β1), collagen I and collagen III; the protocols were as previously described (Wang et al, 2017). Briefly, 40µg of protein was fractionated by 12% SDS-PAGE and then transferred onto PVDF membranes.…”

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats

“…LV tissues were cut into small pieces, fixed with 4% paraformaldehyde, and embedded in paraffin. Hematoxylin-eosin (HE) staining, Masson's trichrome staining, and picrosirius red staining were performed on the 5 μ m thick histological sections to analyze LV fibrosis in the light of our previous method [ 23 ]. Eight paraffin blocks per group were taken for the tissue slide preparation and 9 separate bright field microscopic images per animal were quantified.…”

Relationship between the Expression Level of Calcium Handling Proteins of the Sarcoplasmic Reticulum of Cardiomyocytes and the Structural and Functional State of the Patient Hearts with Permanent Atrial Fibrillation

“…At the same time, in patients with a preserved ejection fraction and AF, the content of SERCA2a in the right atrial myocardium was significantly lower than in patients without rhythm disturbances [7]. Experimental studies have shown that modeling both acute and chronic AF leads to a decrease in the expression of SERCA2a, while overexpression of this protein reduces the AF occurrence rate [8][9][10]. In addition, since the functioning of SERCA2a is associated with significant energy consumption [11], under the conditions of a high frequency of atrial contraction, cardiomyocytes may lack energy supply, which may lead to a decrease in both activity and expression of this protein.…”