Adropin as a therapeutic candidate for HFpEF: evidence of oxidative stress mitigation via Nrf2/HO-1 signaling.

Background: Heart failure with preserved ejection fraction (HFpEF), which accounts for more than half of all heart failure cases worldwide, has emerged as a major public health challenge characterized by substantial morbidity and mortality rates. As adropin is a key regulator of cardiovascular and metabolic homeostasis, this study investigated its therapeutic effects against HFpEF pathogenesis.

Methods: C57BL/6 mice were fed a high-fat diet (60% fat-derived calories) with NG-nitro-L-arginine methyl ester (L-NAME, 0.5 g/L) in drinking water for 8 weeks to induce HFpEF. Adropin-knockout (Ad⁻/⁻) mice were generated, and HFpEF mice received a single intraperitoneal bolus of recombinant adropin (450 nmol kg⁻¹). Cardiac structure and function were quantified by echocardiography. Metabolic status was documented (body weight, fasting glucose, lipids, and systolic/diastolic blood pressure). Myocardial morphology, fibrosis and cardiomyocyte size were examined by hematoxylin‒eosin, Masson's trichrome and wheat‒germ agglutinin staining. Oxidative stress was evaluated with dihydroethidium fluorescence (ROS) and biochemical assays for malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). The protein expression of Nrf2, HO-1, NQO-1 and apoptosis markers (Bcl-2/Bax) was determined by immunoblotting.

Results: HFpEF mice developed significant metabolic disturbances, diastolic dysfunction, myocardial hypertrophy, fibrosis, and increased oxidative stress, alongside markedly reduced serum and myocardial adropin levels. Adropin supplementation improved glucose and lipid metabolism, reduced cardiac hypertrophy and fibrosis, and enhanced diastolic function, whereas adropin knockout exacerbated these pathologies. Mechanistically, adropin activated the Nrf2/HO-1 signaling pathway, increased the expression of antioxidant enzymes (HO-1 and NQO-1), reduced the expression of oxidative stress markers, and regulated apoptosis by increasing Bcl-2 and decreasing Bax expression. HFpEF mice exhibited significant metabolic disturbances, diastolic dysfunction, myocardial hypertrophy, fibrosis, and elevated oxidative stress, alongside markedly reduced serum and myocardial adropin levels. Adropin treatment improved glucose/lipid metabolism, attenuated hypertrophy/fibrosis, and enhanced diastolic function, whereas adropin knockout exacerbated these pathologies. Mechanistically, adropin activated the Nrf2/HO-1 pathway, upregulated antioxidant enzymes (HO-1, NQO-1), reduced oxidative stress markers, and mitigated apoptosis by increasing Bcl-2/Bax ratio.

Conclusion: Adropin improves HFpEF by attenuating metabolic dysregulation, oxidative stress, and myocardial remodeling. Mechanistically, adropin activates the Nrf2/HO-1 pathway, suggesting a novel therapeutic strategy for HFpEF. These findings highlight the potential of adropin to reduce disease burden and improve quality of life in HFpEF patients, addressing critical gaps in current HFpEF management.