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

Sep 29, 2026

Uploaded by Jiven

Atrial fibrillation is the most common cardiac arrhythmia, with energy metabolic disorder contributing to severe clinical progression. Relaxin-2 (RLX) is a peptide hormone activating enzymes linked to cellular energy metabolism, but its effect on atrial myocyte energy metabolism during AF pathogenesis was unknown. In rabbits, RLX treatment reduced RAP-induced AF susceptibility, atrial fibrosis, and electrical remodeling. UHPLC and mechanistic assays showed PPAR signaling activation via RXFP1 regulation, restoring mitochondrial respiration and ATP production while lowering mitochondrial ROS. In tachypacing HL-1 cells, PPARγ overexpression prevented mitochondrial damage and energy metabolic disruption. Serum RLX-2 levels with altered metabolites correlated with AF occurrence in patients.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Objective and background

Methods and key experimental systems

Findings: AF susceptibility, remodeling, and metabolism

Mechanistic pathway: RXFP1-PPARγ-mitochondria

Patient correlation and therapeutic implication

This article is licensed under CC-BY-NC-ND 4.0 [pubs.acs.org/ptsci](pubs.acs.org/ptsci) Article Relaxin‑2 Exhibits a Beneficial Role in Energy Metabolism to Alleviate Atrial Fibrillation Susceptibility Xinbo Zhao,\# Yukai Cao,\# Qiang Gao,\# Xuejie Han, Hang Zhang, Hongyuan Mu, Song Zhang, Xiaoyu Wang, Yue Li, * and Yue Yuan* Cite This: ACS Pharmacol. Transl. Sci. 2025, 8, 368−379 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | 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. KEYWORDS: relaxin-2, atrial fibrillation, energy metabolic remodeling, PPAR, mitochondrial function Atrial fibrillation (AF) is the most common sustained arrhythmia in clinics, with increased incidence and prevalence globally.1,2 AF accounts for substantial morbidity and mortality, such as heart failure and ischemic stroke, resulting in a significant burden on the healthcare system.3,4 Although a variety of available therapeutic approaches for AF include rhythm control, ablation procedures, and anticoagulant drugs to reduce AF recurrence and prevent thromboembolism, each treatment has its own limitations.5,6 There is a substantial unmet need to explore therapeutic innovations to improve optimal AF management. Relaxin-2 (RLX), an endogenous insulin-like hormone peptide, is originally secreted by the corpus luteum to soften the pubic ligament and cervix in response to giving birth.7,8 Studies over the past decade have shown that RLX exerts beneficial effects in cardiovascular diseases such as acute heart failure, diabetic cardiomyopathy, and cardiac arrhythmias.9−11 Preclinical work demonstrates that RLX exhibits antifibrotic and anti-inflammatory properties to reduce the incidence of atrial arrhythmia in various rodent models that already have significant structural abnormalities. 12,

FAQs

What role does energy metabolism play in atrial fibrillation in this study?

The study links atrial energy metabolic disorder to severe AF clinical courses and frames AF as associated with altered energy supply and remodeling of atrial cells.

How was relaxin-2 tested for its effects on AF susceptibility?

Male New Zealand rabbits were assigned to sham, right atrial tachypacing, or tachypacing plus human recombinant relaxin-2 for two weeks, followed by programmed intracardiac stimulation to assess AF susceptibility.

What mechanism explains how relaxin-2 improves mitochondrial energy metabolism?

Relaxin-2 increases PPARγ expression through regulation of RXFP1, which restores mitochondrial respiration and ATP production and reduces mitochondrial reactive oxygen species. It also prevents mitochondrial damage and alleviates energy metabolic disorder when PPARγ is overexpressed in tachypacing HL-1 cells.

Sep 29, 2026

Uploaded by Jiven