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.

Matrix metalloproteinase 3 regulates angiotensin II‑induced myocardial fibrosis cell viability, migration and apoptosis

“…MMP3 and MMP9 are extracellular zinc proteases that serve vital roles in the development and progression of atherosclerosis ( 52 ). Zhang et al ( 53 ) reported that resveratrol downregulated MMP3 and MMP9 expression levels in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells, and reduced LPS-induced MMP3 and MMP9 secretion. The present study indicated that MMP3 and MMP9 expression levels were downregulated by MMP3 knockdown in AngII-treated cells, which suggested that MMP3 knockdown influenced ECM remodeling by regulating MMP3 and MMP9 expression.…”

Increase in Blood‐Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the ERK Signaling Pathway

“…Afterward, we detected the protein level of MMP3, ZO-1, occludin, VE-cadherin, and claudin-5 by Western blot and fluorescence staining. To increase the MMP3 levels, lipopolysaccharide (LPS) in a dose of 100 μ g/mL as a stimulus to increase the MMP3 levels [ 23 , 24 ], and then, the ERK inhibitor FR1080204 [ 25 ] (purchased from Sigma-Aldrich) was administered to investigate the mechanism behind the effects of MMP3 on the BBB.…”

Resveratrol Prevents Campylobacter jejuni-Induced Leaky gut by Restoring Occludin and Claudin-5 in the Paracellular Leak Pathway

“…In general, the mucosal defense against microorganisms can be modulated by increased expression of mucins, tight junctional proteins, secretion of chemokines and cytokines, or release of direct antimicrobials like β-defensins and cathelicidin. We know from other studies that resveratrol affects intracellular signaling pathways, for example, blockage of NFκB activation (Singh et al, 2010), activator protein-1 (Kundu and Surh, 2004), IκBα (Tsai et al, 1999) or TLR4 and STAT3 (Zhang et al, 2019). Notably, a recent study showed the synergistic effect of resveratrol and vitamin D on the heterodimerization of VDR-RXR nuclear factors, which reflected an increase in vitamin D-dependent gene expression involving transactivation by resveratrol (Dampf Stone et al, 2015).…”