Ellagic acid inhibits oxidized low-density lipoprotein (OxLDL)-induced metalloproteinase (MMP) expression by modulating the protein kinase C-α/extracellular signal-regulated kinase/peroxisome proliferator- activated receptor γ/nuclear factor-κB (PKC-α/ERK/PPAR- γ/NF-κB) signaling pathway in endothelial cells

Mei Ying Kuo, Hsiu Chung Ou, Wen Jane Lee, Wei Wen Kuo, Ling Ling Hwang, Tuzz Ying Song, Chih Yang Huang, Tsan Hung Chiu, Kun Ling Tsai, Chiou Sheng Tsai, Wayne Huey Herng Sheu

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Previous studies have shown that vascular endothelium-derived matrix metalloproteinases (MMPs) contribute to the destabilization of atherosclerotic plaques, a key event triggering acute myocardial infarction. In addition, studies have reported that the PKC-MEK-PPAR-γ signaling pathway is involved in oxidized low-density lipoprotein (oxLDL)-induced expression of MMPs. Ellagic acid, a phenolic compound found in fruits and nuts, has potent antioxidant, anti-inflammatory, and anticancerous properties. However, the molecular mechanisms underlying its antiatherogenic effects remain to be clarified. This study aimed to assess whether the effects of ellagic acid on the fibrotic markers MMP-1 andMMP-3 are modulated by the PKC-ERK-PPAR-γ signaling pathway in human umbilical vein endothelial cells (HUVECs) that have been exposed to oxLDL. It was found that ellagic acid significantly inhibited oxLDL-induced expressions of MMP-1 and MMP-3. Pretreatment with ellagic acid and DPI, a well-known ROS inhibitor, attenuated the oxLDL-induced expression and activity of PKC-α. In addition, ellagic acid as well as pharmacological inhibitors of ROS, calcium, and PKC strongly suppressed the oxLDL-induced phosphorylation of extracellular signal-regulated kinase (ERK) and NF-κB activation. Moreover, ellagic acid ameliorated the oxLDL-induced suppression of PPAR-γ expression. In conclusion, the data suggest that ellagic acid elicits its protective effects by modulating the PKC-α/ERK/PPAR-γ/ NF-κB pathway, resulting in the suppression of ROS generation and, ultimately, inhibition of MMP-1 and MMP-3 expression in HUVECs exposed to oxLDL.

Original languageEnglish
Pages (from-to)5100-5108
Number of pages9
JournalJournal of Agricultural and Food Chemistry
Volume59
Issue number9
DOIs
Publication statusPublished - May 11 2011

Fingerprint

Ellagic Acid
Peroxisome Proliferator-Activated Receptors
ellagic acid
Extracellular Signal-Regulated MAP Kinases
Endothelial cells
protein kinase C
Metalloproteases
metalloproteinases
low density lipoprotein
Matrix Metalloproteinases
mitogen-activated protein kinase
Protein Kinase C
endothelial cells
Endothelial Cells
interstitial collagenase
Matrix Metalloproteinase 1
stromelysin 1
Matrix Metalloproteinase 3
Human Umbilical Vein Endothelial Cells
Phosphorylation

Keywords

  • Atherosclerotic plaques
  • Ellagic acid
  • Matrix metalloproteinases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Chemistry(all)

Cite this

Ellagic acid inhibits oxidized low-density lipoprotein (OxLDL)-induced metalloproteinase (MMP) expression by modulating the protein kinase C-α/extracellular signal-regulated kinase/peroxisome proliferator- activated receptor γ/nuclear factor-κB (PKC-α/ERK/PPAR- γ/NF-κB) signaling pathway in endothelial cells. / Kuo, Mei Ying; Ou, Hsiu Chung; Lee, Wen Jane; Kuo, Wei Wen; Hwang, Ling Ling; Song, Tuzz Ying; Huang, Chih Yang; Chiu, Tsan Hung; Tsai, Kun Ling; Tsai, Chiou Sheng; Sheu, Wayne Huey Herng.

In: Journal of Agricultural and Food Chemistry, Vol. 59, No. 9, 11.05.2011, p. 5100-5108.

Research output: Contribution to journalArticle

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abstract = "Previous studies have shown that vascular endothelium-derived matrix metalloproteinases (MMPs) contribute to the destabilization of atherosclerotic plaques, a key event triggering acute myocardial infarction. In addition, studies have reported that the PKC-MEK-PPAR-γ signaling pathway is involved in oxidized low-density lipoprotein (oxLDL)-induced expression of MMPs. Ellagic acid, a phenolic compound found in fruits and nuts, has potent antioxidant, anti-inflammatory, and anticancerous properties. However, the molecular mechanisms underlying its antiatherogenic effects remain to be clarified. This study aimed to assess whether the effects of ellagic acid on the fibrotic markers MMP-1 andMMP-3 are modulated by the PKC-ERK-PPAR-γ signaling pathway in human umbilical vein endothelial cells (HUVECs) that have been exposed to oxLDL. It was found that ellagic acid significantly inhibited oxLDL-induced expressions of MMP-1 and MMP-3. Pretreatment with ellagic acid and DPI, a well-known ROS inhibitor, attenuated the oxLDL-induced expression and activity of PKC-α. In addition, ellagic acid as well as pharmacological inhibitors of ROS, calcium, and PKC strongly suppressed the oxLDL-induced phosphorylation of extracellular signal-regulated kinase (ERK) and NF-κB activation. Moreover, ellagic acid ameliorated the oxLDL-induced suppression of PPAR-γ expression. In conclusion, the data suggest that ellagic acid elicits its protective effects by modulating the PKC-α/ERK/PPAR-γ/ NF-κB pathway, resulting in the suppression of ROS generation and, ultimately, inhibition of MMP-1 and MMP-3 expression in HUVECs exposed to oxLDL.",
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AU - Ou, Hsiu Chung

AU - Lee, Wen Jane

AU - Kuo, Wei Wen

AU - Hwang, Ling Ling

AU - Song, Tuzz Ying

AU - Huang, Chih Yang

AU - Chiu, Tsan Hung

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AU - Tsai, Chiou Sheng

AU - Sheu, Wayne Huey Herng

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AB - Previous studies have shown that vascular endothelium-derived matrix metalloproteinases (MMPs) contribute to the destabilization of atherosclerotic plaques, a key event triggering acute myocardial infarction. In addition, studies have reported that the PKC-MEK-PPAR-γ signaling pathway is involved in oxidized low-density lipoprotein (oxLDL)-induced expression of MMPs. Ellagic acid, a phenolic compound found in fruits and nuts, has potent antioxidant, anti-inflammatory, and anticancerous properties. However, the molecular mechanisms underlying its antiatherogenic effects remain to be clarified. This study aimed to assess whether the effects of ellagic acid on the fibrotic markers MMP-1 andMMP-3 are modulated by the PKC-ERK-PPAR-γ signaling pathway in human umbilical vein endothelial cells (HUVECs) that have been exposed to oxLDL. It was found that ellagic acid significantly inhibited oxLDL-induced expressions of MMP-1 and MMP-3. Pretreatment with ellagic acid and DPI, a well-known ROS inhibitor, attenuated the oxLDL-induced expression and activity of PKC-α. In addition, ellagic acid as well as pharmacological inhibitors of ROS, calcium, and PKC strongly suppressed the oxLDL-induced phosphorylation of extracellular signal-regulated kinase (ERK) and NF-κB activation. Moreover, ellagic acid ameliorated the oxLDL-induced suppression of PPAR-γ expression. In conclusion, the data suggest that ellagic acid elicits its protective effects by modulating the PKC-α/ERK/PPAR-γ/ NF-κB pathway, resulting in the suppression of ROS generation and, ultimately, inhibition of MMP-1 and MMP-3 expression in HUVECs exposed to oxLDL.

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