Relaxin-2 Exhibits a Beneficial Role in Energy Metabolism to Alleviate Atrial Fibrillation Susceptibility

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with energy metabolic disorder leading to severe clinical courses. Relaxin-2 (RLX), a peptide hormone, has been identified to activate crucial enzymes involved in cellular energy metabolism. However, whether relaxin-2 can improve the energy metabolism of atrial myocytes to inhibit AF pathogenesis remains unknown. Male New Zealand rabbits were randomly separated into sham, right atrial tachypacing (RAP), and RAP with a human recombinant relaxin-2 treatment (0.5 mg/kg) group for 2 weeks, and programmed intracardiac stimulation was performed to assess AF susceptibility. Ultrahigh-performance liquid chromatography (UHPLC) was performed to explore potential metabolic profiles in rabbit atria. Histology, transmission electron microscopy (TEM), Western blot, qRT-PCR, and Seahorse assays were used to explain the molecular mechanisms. The downregulated relaxin family peptide receptor 1 (RXFP1) protein was found in the atria of AF patients and rabbits, as well as in tachypacing HL-1 cells. RLX protected against RAP-induced AF with decreased atrial fibrosis and electrical remodeling in rabbits. UHPLC revealed that RLX improved fatty acid and glucose metabolism by activating the PPAR signaling pathway in rabbit atria. Mechanistically, RLX enhanced peroxisome proliferator-activated receptor-γ (PPARγ) expression via regulating RXFP1, which restored mitochondrial respiration and ATP production, along with reduced mitochondrial reactive oxygen species in both rabbit atria and HL-1 cells. Moreover, overexpression of PPARγ in tachypacing HL-1 cells prevented mitochondrial damage and alleviated energy metabolic disorder. Besides, we found that upregulated serum relaxin-2 levels with altered metabolites, including 13S-hydroxyoctadecadienoic acid, prostaglandin E2, glyceric acid, and deoxyribose 1-phosphate, were correlated with AF occurrence in patients. Our study reveals that relaxin-2 attenuates atrial energy metabolic remodeling to prevent AF pathogenesis, which could be considered a potential therapeutic approach in the clinic.