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

Background The 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. Methods MSCs were pretreated with ATV (0.01-10 mu mol/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. Results Autophagy 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. Conclusion The 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.