Protective effects of higenamine combined with [6]-gingerol against doxorubicin-induced mitochondrial dysfunction and toxicity in H9c2 cells and potential mechanisms

Biomed Pharmacother. 2019 Jul;115:108881. doi: 10.1016/j.biopha.2019.108881.

Jianxia Wen ¹, Jian Wang ², Pengyan Li ³, Ruilin Wang ⁴, Jiabo Wang ³, Xuelin Zhou ⁵, Lu Zhang ⁶, Haotian Li ⁷, Shizhang Wei ⁷, Huadan Cai ⁷, Yanling Zhao ⁸

Affiliations

1 College of Pharmacy, Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, China.
2 College of Pharmacy, Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China. Electronic address: jianwang08@163.com.
3 China Military Institute of Chinese Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China.
4 Integrative Medical Center, The Fifth Medical Center of PLA General Hospital, Beijing, China.
5 Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
6 College of Pharmacy, Zhejiang University of Chinese Medicine, Hangzhou, China.
7 Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, China.
8 Department of Pharmacy, The Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: zhaoyl2855@126.com.

PMID: 31028997 DOI: 10.1016/j.biopha.2019.108881

Abstract

Higenamine (HG) is a well-known selective activator of beta2-adrenergic receptor (β2-AR) with a positive inotropic effect. The present study showed that HG combined with [6]-gingerol (HG/[6]-GR) protects H9c2 cells from doxorubicin (DOX)-induced mitochondrial energy metabolism disorder and respiratory dysfunction. H9c2 cells were pretreated with HG/[6]-GR for 2 h before DOX treatment in all procedures. Cell viability was quantified by a cell counting kit‑8 assay. Cardiomyocyte morphology, proliferation, and mitochondrial function were detected by a high content screening (HCS) assay. Cell mitochondrial stress was measured by a Seahorse XFp analyzer. To further investigate the protective mechanism of HG/[6]-GR, mRNA and protein expression levels of PPARα/PGC-1α/SIRT3 pathway-related molecules were detected. The present data demonstrated that protective effects of HG/[6]-GR combination were presented in mitochondria, which increased cell viability, ameliorated DOX-induced mitochondrial dysfunction, increased mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Most importantly, the protective effects were abrogated by GW6471 (a PPARα Inhibitor) and ameliorated by Wy14643 (a PPARα Agonist). Moreover, the combined use of HG and [6]-GR exerted more profound protective effects than either drug as a single agent. In conclusion, the results suggested that HG/[6]-GR ameliorates DOX-induced mitochondrial energy metabolism disorder and respiratory function impairment in H9c2 cells, and it indicated that the protective mechanism may be related to upregulation of the PPARα/PGC-1α/SIRT3 pathway, which promotes mitochondrial energy metabolism and protects against heart failure.

Keywords

Doxorubicin; Energy metabolism; H9c2 cells; Heart failure; Higenamine; [6]-Gingerol.

Products

Cat. No.

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Category/Application
HY-K0301

Cell Counting Kit-8

Cell Proliferation and Cytotoxicity

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