The autoantibody β1-AA contributes to N/OFQ-exacerbated ventricular arrhythmias following acute myocardial ischemia.

Abstract

Ventricular arrhythmias are a primary cause of sudden cardiac death after acute myocardial infarction (AMI). Both β1-adrenergic autoantibodies (β1-AA) and nociceptin/orphanin FQ (N/OFQ) are implicated in AMI, but their potential interaction in ischemic arrhythmogenesis remains unclear. This study investigated the interplay between N/OFQ and β1-AA and the underlying mechanism. A rat model of AMI was established by ligating the left anterior descending coronary artery. Rats were divided into Sham, coronary artery occlusion (CAO), CAO+NOP receptor antagonist (C-24), CAO+β1-AA+metoprolol, CAO+β1-AA+endocytosis inhibitor (Pitstop), and CAO+β1-AA groups. Hemodynamics and ventricular arrhythmias were recorded, and serum levels of N/OFQ and β1-AA were measured by ELISA. The expression and localization of β1-adrenergic receptors (β1-AR) on cardiomyocyte membranes were analyzed by Western blot and immunofluorescence. Serum levels of both N/OFQ and β1-AA were significantly elevated in the CAO group compared to sham. Treatment with the N/OFQ receptor antagonist C-24 suppressed the ischemia-induced increase in β1-AA. The CAO group exhibited a significantly higher incidence of ventricular arrhythmias (VEB, VT/VF) compared to sham and C-24 groups. Administration of exogenous β1-AA further aggravated arrhythmias, which was exacerbated by inhibiting β1-AR internalization with Pitstop. Conversely, the β1-AR blocker metoprolol exerted a protective effect. Western blot and immunofluorescence confirmed that β1-AA and Pitstop treatment increased β1-AR membrane expression, indicating inhibited receptor internalization. During acute myocardial ischemia, N/OFQ is associated with elevated levels of β1-AA, which may contribute to ventricular arrhythmias, potentially via inhibiting the internalization of β1-AR.