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

Abstract

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 {mu}M) 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-{kappa}B and downstream pro-apoptotic signalingmore » 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.« less

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [6]
  1. Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan (China)
  2. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan (China)
  3. Graduate Institute of Basic Medical Science, China Medical University, Taiwan (China)
  4. Department of Obstetrics and Gynecology, China Medical University Hospital, Taiwan (China)
  5. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China)
  6. Department of Metabolism and Endocrinology, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan (China)
Publication Date:
OSTI Identifier:
21460222
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 248; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2010.07.025; PII: S0041-008X(10)00271-1; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; APOPTOSIS; ARTERIOSCLEROSIS; ENDOTHELIUM; INHIBITION; LIPOPROTEINS; OXIDIZERS; PHENOLS; ANIMAL TISSUES; AROMATICS; BODY; CARDIOVASCULAR DISEASES; DISEASES; HYDROXY COMPOUNDS; LIPIDS; ORGANIC COMPOUNDS; PROTEINS; VASCULAR DISEASES

Citation Formats

Ou, Hsiu-Chung, Lee, Wen-Jane, Tunghai University, Taichung, Taiwan, Lee, Shin-Da, Department of Healthcare Administration, Asia University, Taichung, Taiwan, Huang, Chih-Yang, Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Chiu, Tsan-Hung, Tsai, Kun-Ling, Hsu, Wen-Cheng, Sheu, Wayne Huey-Herng, E-mail: whhsheu@mail.cmu.edu.t, Department of Medicine, Chung Shan Medical University, Taichung, Taiwan, Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan, and College of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan. Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.07.025.
Ou, Hsiu-Chung, Lee, Wen-Jane, Tunghai University, Taichung, Taiwan, Lee, Shin-Da, Department of Healthcare Administration, Asia University, Taichung, Taiwan, Huang, Chih-Yang, Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Chiu, Tsan-Hung, Tsai, Kun-Ling, Hsu, Wen-Cheng, Sheu, Wayne Huey-Herng, E-mail: whhsheu@mail.cmu.edu.t, Department of Medicine, Chung Shan Medical University, Taichung, Taiwan, Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan, & College of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan. Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. United States. doi:10.1016/j.taap.2010.07.025.
Ou, Hsiu-Chung, Lee, Wen-Jane, Tunghai University, Taichung, Taiwan, Lee, Shin-Da, Department of Healthcare Administration, Asia University, Taichung, Taiwan, Huang, Chih-Yang, Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Chiu, Tsan-Hung, Tsai, Kun-Ling, Hsu, Wen-Cheng, Sheu, Wayne Huey-Herng, E-mail: whhsheu@mail.cmu.edu.t, Department of Medicine, Chung Shan Medical University, Taichung, Taiwan, Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan, and College of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan. Fri . "Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway". United States. doi:10.1016/j.taap.2010.07.025.
@article{osti_21460222,
title = {Ellagic acid protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway},
author = {Ou, Hsiu-Chung and Lee, Wen-Jane and Tunghai University, Taichung, Taiwan and Lee, Shin-Da and Department of Healthcare Administration, Asia University, Taichung, Taiwan and Huang, Chih-Yang and Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan and Chiu, Tsan-Hung and Tsai, Kun-Ling and Hsu, Wen-Cheng and Sheu, Wayne Huey-Herng, E-mail: whhsheu@mail.cmu.edu.t and Department of Medicine, Chung Shan Medical University, Taichung, Taiwan and Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan and College of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan},
abstractNote = {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 {mu}M) 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-{kappa}B 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.},
doi = {10.1016/j.taap.2010.07.025},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 248,
place = {United States},
year = {2010},
month = {10}
}