Metabolomics coupled with integrated approaches reveal the therapeutic effects of higenamine combined with [6]-gingerol on doxorubicin-induced chronic heart failure in rats

Jianxia Wen,Junjie Hao,Xiao Ma,Jian Wang,Yanling Zhao,Ming Niu,Ying Huang,Ruisheng Li,Ruilin Wang

doi:10.1186/s13020-020-00403-0

Abstract

BackgroundThis study was aimed to investigate the therapeutic effects and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX)—induced chronic heart failure (CHF) in rats.Materials and methodsTherapeutic effects of HG/[6]-GR on hemodynamics indices, serum biochemical indicators, histopathology and TUNEL staining of rats were assessed. Moreover, a UHPLC-Q-TOF/MS-based serum metabolic approach was performed to identify the metabolites and possible pathways of HG/[6]-GR on DOX-induced CHF.ResultsHG/[6]-GR had effects on regulating hemodynamic indices, alleviating serum biochemical indicators, improving the pathological characteristics of heart tissue and reducing the apoptosis of myocardial cells. Serum metabolisms analyses indicated that the therapeutic effects of HG and [6]-GR were mainly associated with the regulation of eight metabolites, including acetylphosphate, 3-Carboxy-1-hydroxypropylthiamine diphosphate, coenzyme A, palmitic acid, PE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, lysoPC(18:1(9Z)), and PC(16:0/16:0). Pathway analysis showed that HG/[6]-GR on CHF treatment was related to twelve pathways, including glycerophospholipid metabolism, fatty acid metabolism, pantothenate and CoA biosynthesis, citrate cycle (TCA cycle), pyruvate metabolism, and arachidonic acid metabolism. Serum metabolites and metabolic pathways regulated by HG/[6]-GR appear to be related to energy metabolism.ConclusionMultivariate statistical analysis has provided new insights for understanding CHF and investigating the therapeutic effects and mechanisms of HG/[6]-GR, which influencing the metabolites and pathways related to energy metabolism pathway.

Highlights

This study was aimed to investigate the therapeutic effects and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX)—induced chronic heart failure (CHF) in rats
Compared with the control group, serum levels of Brain natriuretic peptide (BNP), NT-proBNP, Lactate dehydrogenase (LDH), Creatine kinase-MB (CK-MB), and Aspartate aminotransferase (AST) in the DOX group were significantly increased (P < 0.01) while serum levels of Adenosine triphosphate (ATP), ATPase, NAD, and Nicotinamide adenine dinucleotide (NADH) were decreased in the DOX group (P < 0.01), which indicated the damage of heart function and energy metabolism disorder in DOX group
HG/[6]-GR group was almost equal to the Dobutamine hydrochloride (DH) group, which markedly decreased the serum levels of BNP, NT-proBNP, LDH, CK-MB, and AST but increased the levels of ATP, ATPase, NAD, and NADH compare with HG or [6]-GR used alone (P < 0.05, P < 0.01)

Summary

Introduction

This study was aimed to investigate the therapeutic effects and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX)—induced chronic heart failure (CHF) in rats. Chronic heart failure (CHF) is the terminal stage of various heart diseases It remains a major clinical cause of morbidity, mortality and seriously endangers the health of humans globally [2]. The different kinds of pharmacological agents used for patients with CHF include angiotensin-converting enzyme inhibitors (ACEI), aldosterone antagonists, angiotensin-receptor blockers, aldosterone antagonists, β-blockers, inotropic agents, diuretics, digitalis, nitrates, vasodilators and so on [4, 5]. These agents are expected to be very major treatments, its poor prognosis and few therapeutic options make CHF still a growing global public health concern. The prevention and treatment of CHF remain major issues globally [6]

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