Cucurbitacin-I induces hypertrophy in H9c2 cardiomyoblasts through activation of autophagy via MEK/ERK1/2 signaling pathway.
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.
['Wu|Yao|Y|', 'Chen|Hongying|H|', 'Li|Ruli|R|', 'Wang|Xiaoxiao|X|', 'Li|He|H|', 'Xin|Juanjuan|J|', 'Liu|Zhiqiang|Z|', 'Wu|Sisi|S|', 'Jiang|Wei|W|', 'Zhu|Ling|L|']
D009320:Atrial Natriuretic Factor D001343:Autophagy D006332:Cardiomegaly D048429:Cell Size D002470:Cell Survival D006801:Humans D007093:Imidazoles D048670:MAP Kinase Kinase 4 D020930:MAP Kinase Kinase Kinases D020935:MAP Kinase Signaling System D032386:Myoblasts, Cardiac D020097:Natriuretic Peptide, Brain D047428:Protein Kinase Inhibitors D011725:Pyridines D015398:Signal Transduction D014315:Triterpenes
Cucurbitacin-I Autophagy MEK/ERK1/2 U0126 Cardiomyocyte hypertrophy