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Inhibition of P2X7 receptor mitigates atrial fibrillation susceptibility in isoproterenol-induced rats
Yunping Zhou1, Tianxin Ye1, Fangcong Yu1
1Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
Background:
Atrial fibrillation (AF) is a common cardiac arrhythmia that is characterized by atrial electrical remodeling. The P2X7 receptor (P2X7R), an ATP-gated ion channel, has been implicated in cardiovascular pathologies; however, its role in atrial electrical remodeling remains unclear. This study investigated whether inhibition of P2X7R could mitigate isoproterenol (ISO)-induced atrial electrical remodeling in rats and explored the underlying mechanisms.
Methods:
Two gene expression profiles related to AF (GSE79768 and GSE10598) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using GEO2R. Mendelian randomization (MR) investigated the causal relationship between P2X7R expression and AF. Enrichment analysis was also conducted. An animal model was established via intraperitoneal injection of ISO for 2 weeks. The rats were divided into three groups: control (CTL), ISO, and ISO + Brilliant Blue G (BBG). Cardiac electrophysiological parameters were assessed using programmed electrical stimulation. Myocardial fibrosis and hypertrophy were evaluated using Sirius Red and Wheat Germ Agglutinin staining, respectively. P2X7R abundance was assessed using immunofluorescence, and relevant proteins were detected by Western blotting.
Results:
GEO2R and MR analyses indicated a correlation between P2X7R expression and AF. Rats in the ISO group exhibited increased P2X7R levels, abnormal cardiac electrophysiology, altered ion channel protein expression, myocardial hypertrophy, and fibrosis. Enrichment analysis indicated that oxidative stress responses might be involved, and Western blotting showed significantly elevated levels of NOX, CaMKII, and associated proteins. BBG (P2X7R inhibitor) treatment mitigated these effects.
Conclusions:
P2X7R was associated with AF, and inhibition of P2X7R curbed electrical and structural remodeling in ISO-induced AF, potentially via the NOX/CaMKII pathway.
Insights
Inhibition of the P2X7 receptor (P2X7R) mitigated atrial fibrillation (AF) remodeling in rats. This suggests P2X7R plays a role in AF pathophysiology and could be a therapeutic target.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Atrial fibrillation (AF) is a common arrhythmia linked to atrial electrical remodeling.
- The P2X7 receptor (P2X7R), an ATP-gated ion channel, is implicated in cardiovascular diseases, but its role in AF is unclear.
- This study investigates P2X7R's role in isoproterenol (ISO)-induced atrial electrical remodeling.
Purpose of the Study:
- To determine if P2X7R inhibition can reduce ISO-induced atrial electrical remodeling in a rat model.
- To explore the underlying molecular mechanisms, including the NOX/CaMKII pathway.
Main Methods:
- Gene expression analysis (GEO2R) and Mendelian randomization (MR) were used to assess P2X7R and AF correlation.
- An ISO-induced AF rat model was established, with groups receiving ISO alone or ISO + P2X7R inhibitor (BBG).
- Electrophysiology, cardiac fibrosis, hypertrophy, P2X7R expression, and protein levels (NOX, CaMKII) were evaluated.
Main Results:
- GEO2R and MR analyses confirmed a correlation between P2X7R expression and AF.
- ISO-treated rats showed increased P2X7R, abnormal electrophysiology, hypertrophy, and fibrosis.
- P2X7R inhibition with BBG reversed these detrimental changes, implicating the NOX/CaMKII pathway.
Conclusions:
- P2X7R is associated with atrial fibrillation.
- Inhibiting P2X7R effectively curbed electrical and structural remodeling in ISO-induced AF.
- The NOX/CaMKII pathway is a likely mechanism through which P2X7R influences AF remodeling.
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