EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can downregulate parameters of endothelial dysfunction by modulating LOX-1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 microg/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well-known inhibitor of flavoproteins, suggesting the involvement of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47phox and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino-terminal region of Akt, with maximal induction at about 30 min, and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cytoprotective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-kappaB via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction.
Ou
Hsiu-Chung
HC
Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, and Department of Obstetrics and Gynecology, China Medical University Hospital, 91 Hsueh-Shih Road, Taichung 40202, Taiwan.
Song
Tuzz-Ying
TY
Yeh
Yueh-Chiao
YC
Huang
Chih-Yang
CY
Yang
Shun-Fa
SF
Chiu
Tsan-Hung
TH
Tsai
Kun-Ling
KL
Chen
Kai-Ling
KL
Wu
Yun-Jhen
YJ
Tsai
Chiou-Sheng
CS
Chang
Li-Yun
LY
Kuo
Wei-Wen
WW
Lee
Shin-Da
SD
D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D002392:Catechin; C045651:epigallocatechin gallate