Diosgenin Attenuates Myocardial Cell Apoptosis Triggered by Oxidative Stress through Estrogen Receptor to Activate the PI3K/Akt and ERK Axes

Michael Yu-Chih Chen; Bruce Chi-Kang Tsai; Wei-Wen Kuo; Chia-Hua Kuo; Yueh-Min Lin; Dennis Jine-Yuan Hsieh; Pei-Ying Pai; Shih-Chieh Liao; Shang-En Huang; Shin-Da Lee; Chih-Yang Huang

doi:10.1142/S0192415X23500556

Diosgenin Attenuates Myocardial Cell Apoptosis Triggered by Oxidative Stress through Estrogen Receptor to Activate the PI3K/Akt and ERK Axes

Am J Chin Med. 2023;51(5):1211-1232. doi: 10.1142/S0192415X23500556. Epub 2023 Jun 17.

Authors

Michael Yu-Chih Chen^{1

2}, Bruce Chi-Kang Tsai³, Wei-Wen Kuo^{4

5}, Chia-Hua Kuo⁶, Yueh-Min Lin^{7

8}, Dennis Jine-Yuan Hsieh^{9

10}, Pei-Ying Pai^{11

12}, Shih-Chieh Liao¹³, Shang-En Huang¹⁴, Shin-Da Lee^{15

16

17

18}, Chih-Yang Huang^{3

19

20

21

22}

Affiliations

¹ Department of Cardiology, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan.
² School of Medicine, Tzu Chi University, Hualien 970, Taiwan.
³ Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan.
⁴ Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
⁵ Ph.D. Program for Biotechnology Industry, China Medical University, Taichung 404, Taiwan.
⁶ Laboratory of Exercise Biochemistry, University of Taipei, Taipei 111, Taiwan.
⁷ Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli 356, Taiwan.
⁸ Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan.
⁹ School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan.
¹⁰ Clinical Laboratory, Chung Shan Medical University Hospital, 402 Taichung, Taiwan.
¹¹ School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan.
¹² Division of Cardiovascular Medicine, Department of Medicine, China Medical University Hospital, Taichung 404, Taiwan.
¹³ Department of Social Medicine, School of Medicine, China Medical University, Taichung 404, Taiwan.
¹⁴ Graduate Institute of Chinese Medical Science, China Medical University, Taichung 404, Taiwan.
¹⁵ Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung 404, Taiwan.
¹⁶ School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R. China.
¹⁷ School of Rehabilitation Medicine, Weifang Medical University, Shandong 261053, P. R. China.
¹⁸ Department of Physical Therapy, Asia University, Taichung 413, Taiwan.
¹⁹ Graduate Institute of Medical Science, China Medical University, Taichung 404, Taiwan.
²⁰ Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.
²¹ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 413, Taiwan.
²² Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan.

PMID: 37335210
DOI: 10.1142/S0192415X23500556

Abstract

Cardiovascular diseases in post-menopausal women are on a rise. Oxidative stress is the main contributing factor to the etiology and pathogenesis of cardiovascular diseases. Diosgenin, a member of steroidal sapogenin, is structurally similar to estrogen and has been shown to have antioxidant effects. Therefore, we aimed to investigate the effects of diosgenin in preventing oxidation-induced cardiomyocyte apoptosis and assessed its potential as a substitute substance for estrogen in post-menopausal women. Apoptotic pathways and mitochondrial membrane potential were measured in H9c2 cardiomyoblast cells and neonatal cardiomyocytes treated with diosgenin for 1[Formula: see text]h prior to hydrogen peroxide (H₂O₂) stimulation. H₂O₂-stimulated H9c2 cardiomyoblast cells displayed cytotoxicity and apoptosis via the activation of both Fas-dependent and mitochondria-dependent pathways. Additionally, it led to the instability of the mitochondrial membrane potential. However, the H₂O₂-induced H9c2 cell apoptosis was rescued by diosgenin through IGF1 survival pathway activation. This led to the recovery of the mitochondrial membrane potential by suppressing the Fas-dependent and mitochondria-dependent apoptosis. Diosgenin also inhibited H₂O₂-induced cytotoxicity and apoptosis through the estrogen receptor interaction with PI3K/Akt and extracellular regulated protein kinases 1/2 activation in myocardial cells. In this study, we confirmed that diosgenin attenuated H₂O₂-induced cytotoxicity and apoptosis through estrogen receptors-activated phosphorylation of PI3K/Akt and ERK signaling pathways in myocardial cells via estrogen receptor interaction. All results suggest that H₂O₂-induced myocardial damage is reduced by diosgenin due to its interaction with estrogen receptors to decrease the damage. Herein, we conclude that diosgenin might be a potential substitute substance for estrogen in post-menopausal women to prevent heart diseases.

Keywords: Apoptosis; Chinese Yam Tubers; Dioscorea polystachya; Diosgenin; Menopause; Oxidative Stress.

MeSH terms

Apoptosis
Cardiovascular Diseases*
Diosgenin* / pharmacology
Estrogens / metabolism
Estrogens / pharmacology
Female
Humans
Hydrogen Peroxide / toxicity
Infant, Newborn
Myocytes, Cardiac / metabolism
Oxidative Stress
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Receptors, Estrogen / metabolism

Substances

Proto-Oncogene Proteins c-akt
Receptors, Estrogen
Phosphatidylinositol 3-Kinases
Hydrogen Peroxide
Diosgenin
Estrogens