Atorvastatin induces autophagy of mesenchymal stem cells under hypoxia and serum deprivation conditions by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.

Na LI; Qian Zhang; Haiyan Qian; Chen Jin; Yuejin Yang; Runlin Gao

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Atorvastatin induces autophagy of mesenchymal stem cells under hypoxia and serum deprivation conditions by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.

Author: Na LI ¹ ; Qian ZHANG ¹ ; Haiyan QIAN ¹ ; Chen JIN ¹ ; Yuejin YANG ² ; Runlin GAO ¹
Author Information

1. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
2. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Email: yangyjfw@126.com.
Publication Type:Journal Article
MeSH: Animals; Atorvastatin Calcium; Autophagy; drug effects; Cell Hypoxia; physiology; Cells, Cultured; Flow Cytometry; Heptanoic Acids; pharmacology; MAP Kinase Signaling System; drug effects; Male; Mesenchymal Stromal Cells; cytology; drug effects; ultrastructure; Microscopy, Electron, Transmission; Pyrroles; pharmacology; Rats
From: Chinese Medical Journal 2014;127(6):1046-1051
CountryChina
Language:English
Abstract:
BACKGROUNDThe survival ratio of implanted mesenchymal stem cells (MSCs) in the infarcted myocardium is low. Autophagy is a complex "self-eating" process and can be utilized for cell survival. We have found that atorvastatin (ATV) can effectively activate autophagy to enhance MSCs survival during hypoxia and serum deprivation (H/SD). The mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is a non-canonical autophagy pathway. We hypothesized that the MEK/ERK pathway mediated ATV-induced autophagy of MSCs under H/SD.
METHODSMSCs were pretreated with ATV (0.01-10 µmol/L) under H/SD for three hours. For inhibitor studies, the cells were pre-incubated with the MEK1/2 inhibitor U0126. Cell autophagy was assessed by acidic vesicular organelles (AVO)-positive cells using flow cytometry, autophagy related protein using Western blotting and autophagosome using transmission electron microscopy.
RESULTSAutophagy was elevated in the H/SD group compared with the normal group. ATV further enhanced the autophagic activity as well as the phosphorylation of ERK1/2 evidenced by more AVO-positive cells ((8.63 ± 0.63)% vs. (5.77 ± 0.44)%, P < 0.05), higher LC3-II/LC3-I ratio (4.36 ± 0.31 vs. 2.52 ± 0.18, P < 0.05) and more autophagosomes. And treatment with U0126 downregulated the phosphorylation of ERK1/2 and attenuated ATV-induced autophagy.
CONCLUSIONThe MEK/ERK pathway participates in ATV-induced autophagy in MSCs under H/SD, and modulation of the pathway could be a novel strategy to improve MSCs survival.