Novel role for TRPC4 in regulation of macroautophagy by a small molecule in vascular endothelial cells
Macroautophagy (autophagy) is an important factor affecting the function of vascular endothelial cells (VECs) and must be tightly regulated in these cells. However, the precise mechanisms underlying this process, particularly in the presence of serum, remain obscure. In this study, we identified tra...
Saved in:
Published in | Biochimica et biophysica acta Vol. 1853; no. 2; pp. 377 - 387 |
---|---|
Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
01.02.2015
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Macroautophagy (autophagy) is an important factor affecting the function of vascular endothelial cells (VECs) and must be tightly regulated in these cells. However, the precise mechanisms underlying this process, particularly in the presence of serum, remain obscure. In this study, we identified trans-3,5,4′-trimethoxystilbene (TMS) as a potent small molecule inducer of autophagy in human umbilical vascular endothelial cells (HUVECs) in the presence of serum. Using high-throughput DNA microarray and siRNA transfection technologies, we demonstrated that TMS induced autophagy by up-regulating the expression of the transient receptor potential canonical channel 4 (TRPC4), an important cation channel in HUVECs. In addition, the overexpression of TRPC4 by plasmid transfection also induced autophagy. Mechanistic studies revealed that the up-regulation of TRPC4 increased the intracellular Ca2+ concentration, which, in turn, activated the Ca2+/CaMKKβ/AMPK pathway, leading to mTOR inhibition and autophagy. Our study identifies a novel role for TRPC4 in the regulation of autophagy in VECs. TMS is a useful new tool for investigating the molecular mechanism of autophagy in VECs and may serve as a potential lead compound for developing a class of autophagy inducers to treat autophagy-related diseases.
[Display omitted]
•TMS is a useful tool to investigate autophagy in VECs in the presence of serum.•TRPC4 is a novel regulator of autophagy in VECs.•TRPC4 overexpression induces autophagy via the downstream Ca2+/CaMKKβ/AMPK/mTOR pathway. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0167-4889 0006-3002 1879-2596 |
DOI: | 10.1016/j.bbamcr.2014.10.030 |