title: 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.
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-PPARγ 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 and MMP-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.
authors.affiliation: Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, Taiwan.
authors.forename: Mei-Ying
authors.initials: MY
authors.lastname: Kuo
authors.forename: Hsiu-Chung
authors.initials: HC
authors.lastname: Ou
authors.forename: Wen-Jane
authors.initials: WJ
authors.lastname: Lee
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Hwang
authors.forename: Tuzz-Ying
authors.initials: TY
authors.lastname: Song
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Tsan-Hung
authors.initials: TH
authors.lastname: Chiu
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Tsai
authors.forename: Chiou-Sheng
authors.initials: CS
authors.lastname: Tsai
authors.forename: Wayne Huey-Herng
authors.initials: WH
authors.lastname: Sheu
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D004610:Ellagic Acid / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D045726:Metalloproteases / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008077:Lipoproteins, LDL; D016328:NF-kappa B; D047495:PPAR gamma; C099252:oxidized low density lipoprotein; D004610:Ellagic Acid; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D045726:Metalloproteases