Resveratrol Inhibits MMP3 and MMP9 Expression and Secretion by Suppressing TLR4/NF-κB/STAT3 Activation in Ox-LDL-Treated HUVECs

Abstract

Aim. Resveratrol is a natural plant polyphenol. The present study investigated the effects of resveratrol on the Toll-like receptor 4- (TLR4-) mediated expression and secretion of matrix metalloproteinases (MMPs) in oxidized low-density lipoprotein- (ox-LDL-) treated human umbilical vein endothelial cells (HUVECs). Methods. Protein expression was analyzed by immunoblotting. The secretion of MMPs was measured by an enzyme-linked immunosorbent assay. The animal experiments were performed with and without resveratrol treatment in high-fat chow-fed mice. Results. Resveratrol inhibited the expression of TLR4, MMP3, and MMP9 in ox-LDL- and lipopolysaccharide- (LPS-) treated HUVECs. Resveratrol reduced the secretion of MMP3 and MMP9 that was induced by ox-LDL and LPS. The TLR4 inhibitor CLI-095 similarly suppressed the expression and secretion of MMP3 and MMP9 in ox-LDL- and LPS-treated HUVECs. Resveratrol attenuated the phosphorylation of the transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) that was induced by ox-LDL and LPS. Resveratrol recovered Sirt1 expression. In the animal experiments, resveratrol decreased TLR4 expression in the aorta, MMP9 levels in plasma, and vascular structural changes in high-fat chow-fed mice, with no significant effect on plasma MMP3 levels. Conclusion. Resveratrol inhibited the TLR4-mediated expression and secretion of MMP3 and MMP9 in ox-LDL-treated HUVECs. The mechanism of action of resveratrol may be associated with the suppression of NF-κB and STAT3 phosphorylation and restoration of Sirt1 expression. Resveratrol exerts protective effects against vascular structural changes in high-fat chow-fed mice.