5-Aminolevulinic Acid Combined with Sodium Ferrous Citrate Ameliorates H₂O₂-Induced Cardiomyocyte Hypertrophy via Activation of the MAPK/Nrf2/HO-1 Pathway

Authors

Mingyi Zhao
Huiming Guo
Jimei Chen
Jinju Wang, Wright State University - Main CampusFollow
Huanlei Huang
Shao-yi Zheng
Mingyan Hei
Jiaxin Li
Shuai Huang
Jiani Li
Xiaotang Ma
Yanfang Chen, Wright State University - Main CampusFollow
Lingling Zhao
Jian Zhuang
Ping Zhu

Document Type

Article

Publication Date

4-15-2015

Abstract

Hydrogen peroxide (H_²O₂) causes cell damage via oxidative stress. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that can protect cardiomyocytes against oxidative stress. In this study, we investigated whether the heme precursor 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) could protect cardiomyocytes from H_²O₂-induced hypertrophy via modulation of HO-1 expression. HL-1 cells pretreated with/without 5-ALA and SFC were exposed to H₂O₂ to induce a cardiomyocyte hypertrophy model. Hypertrophy was evaluated by planar morphometry, 3H-leucine incorporation, and RT-PCR analysis of hypertrophy-related gene expressions. Reactive oxygen species (ROS) production was assessed by 5/6-chloromethyl-2′,7′-ichlorodihydrofluorescein diacetate acetylester. HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expressions were analyzed by Western blot. In our experiments, HL-1 cells were transfected with Nrf2 siRNA or treated with a signal pathway inhibitor. We found several results. 1) ROS production, cell surface area, protein synthesis, and expressions of hypertrophic marker genes, including atrial natriuretic peptide, brain natriuretic peptide, atrial natriuretic factor, and β-myosin heavy chain, were decreased in HL-1 cells pretreated with 5-ALA and SFC. 2) 5-ALA and SFC increased HO-1 expression in a dose- and time-dependent manner, associated with upregulation of Nrf2. Notably, Nrf2 siRNA dramatically reduced HO-1 expression in HL-1 cells. 3) ERK1/2, p38, and SAPK/JNK signaling pathways were activated and modulate 5-ALA- and SFC-enhanced HO-1 expression. SB203580 (p38 kinase), PD98059 (ERK), or SP600125 (JNK) inhibitors significantly reduced this effect. In conclusion, our data suggest that 5-ALA and SFC protect HL-1 cells from H₂O₂-induced cardiac hypertrophy via activation of the MAPK/Nrf2/HO-1 signaling pathway.

Repository Citation

Zhao, M., Guo, H., Chen, J., Wang, J., Huang, H., Zheng, S., Hei, M., Li, J., Huang, S., Li, J., Ma, X., Chen, Y., Zhao, L., Zhuang, J., & Zhu, P. (2015). 5-Aminolevulinic Acid Combined with Sodium Ferrous Citrate Ameliorates H₂O₂-Induced Cardiomyocyte Hypertrophy via Activation of the MAPK/Nrf2/HO-1 Pathway. American Journal of Physiology - Cell Physiology, 308 (8), C665-C672.
https://corescholar.libraries.wright.edu/ptox/81

DOI

10.1152/ajpcell.00369.2014