Salsolinol Attenuates Doxorubicin-Induced Chronic Heart Failure in Rats and Improves Mitochondrial Function in H9c2 Cardiomyocytes.

Yuxue Yang,Lu Zhang,Jianyu Li,Honghong Liu,Jiabo Wang,Yingying Wang,Ruisheng Li,Yanling Zhao,Huadan Cai,Jianxia Wen

doi:10.3389/fphar.2019.01135

Abstract

Backgrounds: Salsolinol (SAL), a plant-based isoquinoline alkaloid, was initially isolated from Aconiti Lateralis Radix Praeparata (ALRP) and identified as the active cardiotonic component of ALRP. This study was aimed to explore the therapeutic effect and mechanism by which SAL attenuates doxorubicin (DOX)-induced chronic heart failure (CHF) in rats and improves mitochondrial function in H9c2 cardiomyocytes. Methods: Rats were intraperitoneally injected with DOX to establish CHF model. Therapeutic effects of SAL on hemodynamic parameters, serum indices, and the histopathology of the heart were analyzed in vivo. Moreover, H9c2 cardiomyocytes were pretreated with SAL for 2 h before DOX treatment in all procedures in vitro. Cell viability, cardiomyocyte morphology, proliferation, and mitochondrial function were detected by a high-content screening (HCS) assay. In addition, a Seahorse Extracellular Flux (XFp) analyzer was used to evaluate the cell energy respiratory and energy metabolism function. To further investigate the potential mechanism of SAL, relative mRNA and protein expression of key enzymes in the tricarboxylic acid cycle in vivo and mitochondrial calcium uniporter (MCU) signaling pathway-related molecules in vitro were detected. Results: The present data demonstrated the pharmacological effect of SAL on DOX-induced CHF, which was through ameliorating heart function, downregulating serum levels of myocardial injury markers, alleviating histological injury to the heart, increasing the relative mRNA expression levels of key enzymes downstream of the tricarboxylic acid cycle in vivo, and thus enhancing myocardial energy metabolism. In addition, SAL had effects on increasing cell viability, ameliorating DOX-induced mitochondrial dysfunction, and increasing mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in H9c2 cardiomyocyte. Moreover, we found that SAL might have an effect on improving mitochondrial respiratory function and energy metabolism via inhibiting excessive activation of MCU pathway in H9c2 cells. However, the protective effect could be ameliorated by ruthenium red (an MCU inhibitor) and abrogated by spermine (an MCU activator) in vitro. Conclusion: The therapeutic effects of SAL on CHF are possibly related to ameliorating cardiomyocyte function resulting in promotion of mitochondrial respiratory and energy metabolism. Furthermore, the potential mechanism might be related to downregulating MCU pathway. These findings may provide a potential therapy for CHF.

Highlights

Chronic heart failure (CHF), the most common form of cardiovascular disease, is a serious health problem worldwide, with rising incidence and prevalence (Stephan et al, 2017; Zhang et al, 2018)
The results indicated that the therapeutic effects of SAL on CHF are possibly related to ameliorating cardiomyocyte function resulting in promotion of mitochondrial respiratory and energy metabolism
To identify whether CHF model had been successfully established, the role of DOX in rats was examined by hemodynamic parameters of cardiac function, including left ventricular systolic pressure (LVSP), left ventricle end diastolic pressure (LVEDP), and ± dp/dtmax

Summary

Introduction

Chronic heart failure (CHF), the most common form of cardiovascular disease, is a serious health problem worldwide, with rising incidence and prevalence (Stephan et al, 2017; Zhang et al, 2018). The heart is the main energy-consuming organ of one’s body, and sufficient energy supply is a normal guarantee for maintaining its own needs and pumping function. The insufficient myocardial energy supply or metabolic imbalance will lead to the abnormal structure and function of the heart and eventually lead to the occurrence of HF (Watanabe et al, 2010). As energy metabolism is affected during compensated hypertrophy and cardiac failure, compounds that can promote mitochondrial energy metabolism may be potential drugs for the treatment of HF (Neubauer et al, 1997; Kalsi et al, 1999)

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