Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway

Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized low-density lipoprotein (oxLDL) promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. Previous studies have shown that t...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2010-10, Vol.248 (2), p.134-143
Main Authors: Ou, Hsiu-Chung, Lee, Wen-Jane, Lee, Shin-Da, Huang, Chih-Yang, Chiu, Tsan-Hung, Tsai, Kun-Ling, Hsu, Wen-Cheng, Sheu, Wayne Huey-Herng
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
60 APPLIED LIFE SCIENCES
Akt
ANIMAL TISSUES
ANTIOXIDANTS
APOPTOSIS
Apoptosis - drug effects
AROMATICS
ARTERIOSCLEROSIS
Biological and medical sciences
BODY
Calcium - metabolism
CARDIOVASCULAR DISEASES
Caspase 3 - metabolism
Cells, Cultured
Chemical mutagenesis
DISEASES
Ellagic acid
Ellagic Acid - pharmacology
Endothelial Cells - drug effects
Endothelial Cells - enzymology
Endothelial Cells - metabolism
ENDOTHELIUM
Enzyme Activation - drug effects
Humans
HYDROXY COMPOUNDS
INHIBITION
LIPIDS
LIPOPROTEINS
Lipoproteins, LDL - metabolism
Lipoproteins, LDL - toxicity
Medical sciences
Membrane Potential, Mitochondrial - drug effects
NF-kappa B - metabolism
Nitric Oxide Synthase Type III - metabolism
ORGANIC COMPOUNDS
Oxidation-Reduction - drug effects
OXIDIZERS
oxLDL
PHENOLS
Phosphatidylinositol 3-Kinases - metabolism
Protective Agents - pharmacology
PROTEINS
Proto-Oncogene Proteins c-akt - metabolism
Reactive Oxygen Species - metabolism
ROS
Signal Transduction - drug effects
Toxicology
VASCULAR DISEASES
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Summary:Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized low-density lipoprotein (oxLDL) promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. Previous studies have shown that the phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase/nitric oxide (PI3K/Akt/eNOS/NO) pathway is involved in oxLDL-induced endothelial apoptosis. Ellagic acid, a natural polyphenol found in berries and nuts, has in recent years been the subject of intense research within the fields of cancer and inflammation. However, its protective effects against oxLDL-induced injury in vascular endothelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effect of ellagic acid in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL and explored the possible mechanisms. Our results showed that pretreatment with ellagic acid (5–20 μM) significantly attenuated oxLDL-induced cytotoxicity, apoptotic features, and generation of reactive oxygen species (ROS). In addition, the anti-apoptotic effect of ellagic acid was partially inhibited by a PI3K inhibitor (wortmannin) and a specific eNOS inhibitor (cavtratin) but not by an ERK inhibitor (PD98059). In exploring the underlying mechanisms of ellagic acid action, we found that oxLDL decreased Akt and eNOS phosphorylation, which in turn activated NF-κB and downstream pro-apoptotic signaling events including calcium accumulation, destabilization of mitochondrial permeability, and disruption of the balance between pro- and anti-apoptotic Bcl-2 proteins. Those alterations induced by oxLDL, however, were attenuated by pretreatment with ellagic acid. The inhibition of oxLDL-induced endothelial apoptosis by ellagic acid is due at least in part to its anti-oxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2010.07.025