Lingguizhugan decoction dynamically regulates MAPKs and AKT signaling pathways to retrogress the pathological progression of cardiac hypertrophy to heart failure

Yao Chen; Lin Li; Cunyu Hu; Xin Zhao; Peng Zhang; Yanxu Chang; Ye Shang; Yafen Pang; Weiqiang Qian; Xianzhe Qiu; Hongxia Zhang; Deqin Zhang; Shukun Zhang; Yuhong Li

doi:10.1016/j.phymed.2022.153951

Lingguizhugan decoction dynamically regulates MAPKs and AKT signaling pathways to retrogress the pathological progression of cardiac hypertrophy to heart failure

Phytomedicine. 2022 Apr:98:153951. doi: 10.1016/j.phymed.2022.153951. Epub 2022 Jan 21.

Authors

Yao Chen¹, Lin Li², Cunyu Hu¹, Xin Zhao², Peng Zhang¹, Yanxu Chang³, Ye Shang¹, Yafen Pang¹, Weiqiang Qian¹, Xianzhe Qiu¹, Hongxia Zhang⁴, Deqin Zhang³, Shukun Zhang⁵, Yuhong Li⁶

Affiliations

¹ Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China.
² Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China.
³ Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China.
⁴ Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, 69 Zeng Chan Road, He Bei, Tianjin 300250, China.
⁵ Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, 6 Chang Jiang Road, Nan Kai, Tianjin 300100, China. Electronic address: shu1971@163.com.
⁶ Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China. Electronic address: liyuhong@tjutcm.edu.cn.

PMID: 35131606
DOI: 10.1016/j.phymed.2022.153951

Abstract

Background: Heart failure (HF) is a grave health concern, with high morbidity and mortality, calling for the urgent need for new and alternative pharmacotherapies. Lingguizhugan decoction (LD) is a classic Chinese formula clinically used to treat HF. However, the underlying mechanisms involved are not fully elucidated.

Purpose: Based on that, this study aims to investigate the effects and underlying mechanisms of LD on HF.

Methods: After confirming the therapeutic benefits of LD in transverse aortic constriction (TAC)-induced HF mice, network pharmacology and transcriptomic analyzes were utilized to predict the potential molecular targets and pathways of LD treatment in failing hearts, which were evaluated at 3 and 9 w after TAC. UHPLC-QE-MS analysis was utilized to detect bioactive ingredients from LD and plasma of LD-treated rats.

Results: Our results showed that LD markedly alleviated cardiac dysfunction via down-regulating CH-related genes and proteins expression in TAC mice. Significantly, cardiac hypertrophy signaling, including AKT and MAPKs signaling pathways, were identified, suggesting the pathways as likely regulatory targets for LD treatment. LD inhibited p38 and ERK phosphorylated expression levels, with the latter effect likely dependent on regulation of AMPK. Interestingly, LD exerted a dual modulatory role in the AKT-GSK3β/mTOR/P70S6K signaling pathway's regulation, which was characterized by stimulatory activity at 3 w and inhibitory effects at 9 w. Finally, 15 bioactive compounds detected from plasma were predicted as the potential regulators of the AKT-GSK3β/mTOR and MAPKs signaling pathways.

Conclusion: Our study shows LD's therapeutic efficacy in failing hearts, signifies LD as HF medication that acts dynamically by balancing AKT-GSK3β/mTOR/P70S6K and MAPKs pathways, and reveals possible bioactive compounds responsible for LD effects on HF.

Keywords: AKT-GSK3β/mTOR/P70S6K; Cardiac hypertrophy; Heart failure; Lingguizhugan decoction; MAPKs; Pressure overload.