Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells.
Chemical modulators of macroautophagy (herein referred to as autophagy) have aroused widespread interest among biologists and clinical physicians because of their potential for disease therapy. Pterostilbene (PT), a natural small-molecular compound, has been demonstrated to inhibit oxidized low-density lipoprotein (oxLDL)-induced apoptosis in vascular endothelial cells (VECs). The aim of the present study was to investigate whether and how PT could induce VEC autophagy. PT at 0.5 or 1 μM could effectively induce autophagosome formation in human umbilical vein VECs (HUVECs). PT promoted autophagy via a rapid elevation in intracellular calcium ([Ca(2+)]i) concentration and subsequent AMP-activated protein kinase α1 subunit (AMPKα1) activation, which in turn inhibited mammalian target of rapamycin, a potent inhibitor of autophagy. PT-induced AMPKα1 activation and autophagy were refractory to the depletion of serine/threonine kinase 11 but depended on calcium/calmodulin-dependent protein kinase kinase-β activation. Interestingly, PT stimulated cytoprotective autophagy so as to aid in the removal of accumulated toxic oxLDL and inhibit apoptosis in HUVECs. Our study provides a potent small molecule enhancer of autophagy and a novel useful tool in exploring the molecular mechanisms for crosstalk between apoptosis and autophagy. PT could serve as a potential lead compound for developing a class of autophagy regulator as autophagy-related diseases therapy.
College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001, China. chaperones@163.com
Lu
L
Zhang
LiuQing
L
Cui
GuangZhou
G
Zhou
HongJuan
H
Jing
YuQi
Y
Guo
WenKai
W
Sun
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019610:Cytoprotection; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; D013267:Stilbenes; C099252:oxidized low density lipoprotein; C107773:pterostilbene; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human