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.