Cucurbitacin-I induces hypertrophy in H9c2 cardiomyoblasts through activation of autophagy via MEK/ERK1/2 signaling pathway.

Abstract

Cucurbitacin-I, a natural triterpenoids initially identified in medicinal plants, shows a potent anticancer effect on a variety of cancer cell types. Nevertheless, the cardiotoxicity of cucurbitacin-I has not heretofore been reported. In this study, the mechanisms of cucurbitacin-I-induced cardiotoxicity were examined by investigating the role of MAPK-autophagy-dependent pathways. After being treated with 0.1-0.3μM cucurbitacin-I for 48h, H9c2 cells showed a gradual decrease in the cell viabilities, a gradual increase in cell size, and mRNA expression of ANP and BNP (cardiac hypertrophic markers). Cucurbitacin-I concentration-dependent apoptosis of H9c2 cells was also observed. The increased apoptosis of H9c2 cells was paralleling with the gradually strong autophagy levels. Furthermore, an autophagy inhibitor, 3-MA, was used to block the cucurbitacin-I-stirred autophagy, and then the hypertrophy and apoptosis induced by 0.3μM cucurbitacin-I were significantly attenuated. In addition, cucurbitacin-I exposure also activated the MAPK signaling pathways, including ERK1/2, JNK, and p38 kinases. Interestingly, only the ERK inhibitor U0126, but not the JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580, weakened the induction of 0.3μM cucurbitacin-I in hypertrophy, autophagy and apoptosis. Our findings suggest that cucurbitacin-I can increase the autophagy levels of H9c2 cells, most likely, through the activation of an ERK-autophagy dependent pathway, which results in the hypertrophy and apoptosis of cardiomyocytes.

• Authors: Yao Wu, Hongying Chen, Ruli Li, Xiaoxiao Wang, He Li, Juanjuan Xin, Zhiqiang Liu, Sisi Wu, Wei Jiang, Ling Zhu
• Journal: Toxicology letters (Toxicol Lett) Vol. 264 Pg. 87-98 (Dec 15 2016) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 27836799 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Imidazoles
• Protein Kinase Inhibitors
• Pyridines
• Triterpenes
• Natriuretic Peptide, Brain
• Atrial Natriuretic Factor
• MAP Kinase Kinase Kinases
• MAP Kinase Kinase 4
• SB 203580
• cucurbitacin I

Topics

• Atrial Natriuretic Factor (biosynthesis)
• Autophagy (drug effects)
• Cardiomegaly (chemically induced, pathology)
• Cell Size (drug effects)
• Cell Survival (drug effects)
• Humans
• Imidazoles (pharmacology)
• MAP Kinase Kinase 4 (antagonists & inhibitors)
• MAP Kinase Kinase Kinases (drug effects)
• MAP Kinase Signaling System (drug effects)
• Myoblasts, Cardiac (drug effects)
• Natriuretic Peptide, Brain (biosynthesis)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)