The mechanism of Renshen-Fuzi herb pair for treating heart failure-Integrating a cardiovascular pharmacological assessment with serum metabolomics

Xiaofei Chen; Yulong Chen; Shiyang Xie; Xiaoyan Wang; Yali Wu; Hui Zhang; Ya Zhao; Jinhao Jia; Bin Wang; Weixia Li; Jinfa Tang; Xiaohe Xiao

doi:10.3389/fphar.2022.995796

The mechanism of Renshen-Fuzi herb pair for treating heart failure-Integrating a cardiovascular pharmacological assessment with serum metabolomics

Front Pharmacol. 2022 Dec 5:13:995796. doi: 10.3389/fphar.2022.995796. eCollection 2022.

Authors

Xiaofei Chen^{1

2}, Yulong Chen³, Shiyang Xie², Xiaoyan Wang², Yali Wu², Hui Zhang², Ya Zhao², Jinhao Jia³, Bin Wang³, Weixia Li², Jinfa Tang², Xiaohe Xiao⁴

Affiliations

¹ College of Medicine, Chengdu University of Chinese Medicine, Chengdu, China.
² Henan Province Engineering Laboratory for Clinical Evaluation Technology of Chinese Medicine, Henan Province Engineering Research Center for Clinical Application, Evaluation and Transformation of Traditional Chinese Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.
³ College of Medicine, Henan University of Chinese Medicine, Zhengzhou, China.
⁴ Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Abstract

Background: Renshen-Fuzi herb pair (RS-FZ) is often used in the clinical treatment of heart failure (HF) and has a remarkable therapeutic effect. However, the mechanism of RS-FZ for treating HF remains unclear. In our study, we explored the mechanism of RS-FZ for treating HF. Methods: Evaluation of RS-FZ efficacy by cardiovascular pharmacology. Moreover, Global metabolomics profiling of the serum was detected by UPLC-QTOF/MS. Multivariate statistics analyzed the specific serum metabolites and corresponding metabolic pathways. Combining serum metabolomics with network pharmacology, animal experiments screened and validated the critical targets of RS-FZ intervention in HF. Results: RS-FZ significantly ameliorated myocardial fibrosis, enhanced cardiac function, and reduced the serum HF marker (brain natriuretic peptide) level in rats with HF. Through topological analysis of the "Metabolite-Target-Component" interaction network, we found that 79 compounds of RS-FZ directly regulated the downstream specific serum metabolites by acting on four critical target proteins (CYP2D6, EPHX2, MAOB, and ENPP2). The immunohistochemistry results showed that RS-FZ observably improved the expression of CYP2D6 and ENPP2 proteins while decreasing the expression of EPHX2 and MAOB proteins dramatically. Conclusion: The integrated cardiovascular pharmacological assessment with serum metabolomics revealed that RS-FZ plays a crucial role in the treatment of HF by intervening in CYP2D6, EPHX2, MAOB, and ENPP2 target proteins. It provides a theoretical basis for RS-FZ for treating HF.

Keywords: Aconitum carmichaeli Debeaux; Panax ginseng C.A.Mey.; cardiovascular pharmacological; combination mechanisms; heart failure; serum metabolomics.