AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis

Wuping Tan; Yijun Wang; Siyi Cheng; Zhihao Liu; Mengjie Xie; Lingpeng Song; Qinfang Qiu; Xiaofei Wang; Zeyan Li; Tianyuan Liu; Fuding Guo; Jun Wang; Xiaoya Zhou

doi:10.1016/j.jare.2024.02.015

AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis

J Adv Res. 2024 Feb 20:S2090-1232(24)00077-8. doi: 10.1016/j.jare.2024.02.015. Online ahead of print.

Authors

Wuping Tan¹, Yijun Wang¹, Siyi Cheng¹, Zhihao Liu¹, Mengjie Xie¹, Lingpeng Song¹, Qinfang Qiu¹, Xiaofei Wang¹, Zeyan Li¹, Tianyuan Liu¹, Fuding Guo², Jun Wang³, Xiaoya Zhou⁴

Affiliations

¹ Department of Cardiology, Renmin Hospital of Wuhan University, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, China; Taikang Center for Life and Medical Sciences, Wuhan University, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, China; Hubei Key Laboratory of Cardiology, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
² Department of Cardiology, Renmin Hospital of Wuhan University, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, China; Taikang Center for Life and Medical Sciences, Wuhan University, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, China; Hubei Key Laboratory of Cardiology, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. Electronic address: guofuding@whu.edu.cn.
³ Department of Cardiology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China. Electronic address: Junwang0607@whu.edu.cn.
⁴ Department of Cardiology, Renmin Hospital of Wuhan University, China; Institute of Molecular Medicine, Renmin Hospital of Wuhan University, China; Hubei Key Laboratory of Autonomic Nervous System Modulation, China; Taikang Center for Life and Medical Sciences, Wuhan University, China; Cardiac Autonomic Nervous System Research Center of Wuhan University, China; Hubei Key Laboratory of Cardiology, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. Electronic address: whuzhouxiaoya@whu.edu.cn.

PMID: 38382593
DOI: 10.1016/j.jare.2024.02.015

Abstract

Introduction: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis.

Objectives: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model.

Methods: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods.

Results: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively.

Conclusions: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Keywords: AdipoRon; Fatty acid oxidation; Heart failure with preserved ejection fraction; Lipid accumulation; Metabolic syndrome.