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Front. Physiol. | doi: 10.3389/fphys.2018.00307

Pravastatin protects against avascular necrosis of femoral head via autophagy

 Yun Liao1, 2, Ping Zhang1,  Bo Yuan1, Ling Li1* and  Shisan (Bob) Bao1, 3*
  • 1Tongren Hospital, China
  • 2Shanghai Tenth People's Hospital, Tongji University, China
  • 3Bosch Institute, University of Sydney, Australia

Autophagy serves as a stress response and may contribute to the pathogenesis of avascular necrosis of the femoral head induced by steroids. Statins promote angiogenesis and ameliorate endothelial functions through apoptosis inhibition and necrosis of endothelial progenitor cells, however the process used by statins to modulate autophagy in avascular necrosis of the femoral head remains unclear. This manuscript determines whether pravastatin protects against dexamethasone-induced avascular necrosis of the femoral head by activating endothelial progenitor cell autophagy. Pravastatin was observed to enhance the autophagy activity in endothelial progenitor cells, specifically by upregulating LC3-II/Beclin-1 (autophagy related proteins), and autophagosome formation in vivo and in vitro. An autophagy inhibitor, 3-MA, reduced pravastatin protection in endothelial progenitor cells exposed to dexamethasone by attenuating pravastatin-induced autophagy. Adenosine monophosphate-activated protein kinase (AMPK) is a key autophagy regulator by sensing cellular energy changes, and indirectly suppressing activation of the mammalian target of rapamycin (mTOR). We found that phosphorylation of AMPK was upregulated however phosphorylation of mTOR was downregulated in pravastatin-treated endothelial progenitor cells, which was attenuated by AMPK inhibitor compound C. Furthermore, liver kinase B1 (a phosphorylase of AMPK) knockdown eliminated pravastatin regulated autophagy protein LC3-II in endothelial progenitor cells in vitro. We therefore demonstrated pravastatin rescued endothelial progenitor cells from dexamethasone-induced autophagy dysfunction through the AMPK-mTOR signaling pathway in a liver kinase B1-dependent manner. Our results provide useful information for the development of novel therapeutics for management of glucocorticoids-induced avascular necrosis of the femoral head.
ANFH: avascular necrosis of the femoral head
ANFH-PS: avascular necrosis of the femoral head and pravastatin
EPCs: endothelial progenitor cells
BM-EPCs: bone Marrow derived-endothelial progenitor cells
GCs: glucocorticoids
Dex: dexamethasone
LC3: microtubule-associated protein light chain 3
AMPK: adenosine monophosphate-activated protein kinase
mTOR: mammalian target of rapamycin
LKB1: liver kinase B1
CaMKKβ: calcium/calmodulin-dependent protein kinase kinase β
MRI: magnetic resonance imaging
STIR: short-tau inversion recovery
LDH: lactate dehydrogenase

Keywords: Autophagy, Avascular necrosis of the femoral head, Pravastatin, endothelial progenitor cells, AMPK, mTOR, LKB1

Received: 27 Sep 2017; Accepted: 14 Mar 2018.

Edited by:

Giovanni Li Volti, Università degli Studi di Catania, Italy

Reviewed by:

Manuel Ramírez-Sánchez, Universidad de Jaén, Spain
Yiguang Lin, University of Technology Sydney, Australia  

Copyright: © 2018 Liao, Zhang, Yuan, Li and Bao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Ling Li, Tongren Hospital, Changning, China,
Dr. Shisan (Bob) Bao, Tongren Hospital, Changning, China,