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The effect of resveratrol on expression of matrix metalloproteinase 9 and its tissue inhibitors in vascular smooth muscle cells.

ABSTRACT: BACKGROUND:Matrix metalloproteinase 9 (MMP-9) is involved in extracellular matrix degradation and remodeling. An increase in MMP-9 expression by vascular component cells plays an important role in atherosclerotic plaque formation and rupture. Resveratrol, a polyphenolic substance, was suggested to play a role in preventing the progress of atherosclerotic disease. The aim of this study was to investigate the effect of resveratrol on MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) in vascular smooth muscle cells (VSMCs) after treatment with H2O2. METHODS:Cultured VSMCs were pre-treated with 0.2 mM of H2O2 before stimulation with different concentration of resveratrol. Expression of MMP-9, TIMP-1, and TIMP-3 genes were measured using real-time polymerase chain reaction (PCR) method, and MMP-9 protein level was detected using western blot analysis. RESULTS:Resveratrol at 120 ?mol/l concentration reduced the elevated level of MMP-9 induced by H2O2 in VSMCs as 1.85 ± 0.35 folds (P < 0.050) and 8.70 ± 1.20 folds (P < 0.050) after 24 and 48 hours, respectively. Resveratrol increased the diminished level of TIMP-1 induced by H2O2 as 2.5 ± 0.48 folds following the treatment with 120 ?mol/l after 48 hours (P < 0.050). CONCLUSION:Resveratrol as an antioxidant can decrease MMP-9 production, not only by suppressing MMP-9 expression, but also by augmenting TIMP-1 production. Altogether, resveratrol as an antioxidant can regulate the MMP-9/TIMP-1 balance, and may be considered as a preservative agent in the treatment and prevention of atherosclerosis.

SUBMITTER: Farrokhi E

PROVIDER: S-EPMC6312567 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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The effect of resveratrol on expression of matrix metalloproteinase 9 and its tissue inhibitors in vascular smooth muscle cells.

Farrokhi Effat E Ghatreh-Samani Keihan K Salehi-Vanani Najmeh N Mahmoodi Amin A

ARYA atherosclerosis 20180701 4

<h4>Background</h4>Matrix metalloproteinase 9 (MMP-9) is involved in extracellular matrix degradation and remodeling. An increase in MMP-9 expression by vascular component cells plays an important role in atherosclerotic plaque formation and rupture. Resveratrol, a polyphenolic substance, was suggested to play a role in preventing the progress of atherosclerotic disease. The aim of this study was to investigate the effect of resveratrol on MMP-9 and tissue inhibitors of metalloproteinases (TIMPs ...[more]

PMID: 30627191

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Project description:We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

Project description:Over expression of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) in vascular smooth muscle cells (VSMCs) induces apoptosis and reduces neointima formation occurring after saphenous vein interposition grafting or coronary stenting. In studies to address the mechanism of TIMP-3-driven apoptosis in human VSMCs we find that TIMP-3 increased activation of caspase-8 and apoptosis was inhibited by expression of Cytokine response modifier A (CrmA) and dominant negative FAS-Associated protein with Death Domain (FADD). TIMP-3 induced apoptosis did not cause mitochondrial depolarisation, increase activation of caspase-9 and was not inhibited by over-expression of B-cell Lymphoma 2 (Bcl2), indicating a mitochondrial independent/type-I death receptor pathway. TIMP-3 increased levels of the First Apoptosis Signal receptor (FAS) and depletion of FAS with shRNA showed TIMP-3-induced apoptosis was FAS dependent. TIMP-3 induced formation of the Death-Inducing Signalling Complex (DISC), as detected by immunoprecipitation and by immunofluorescence. Cellular-FADD-like IL-1 converting enzyme-Like Inhibitory Protein (c-FLIP) localised with FAS at the cell periphery in the absence of TIMP-3 and this localisation was lost on TIMP-3 expression with c-FLIP adopting a perinuclear localisation. Although TIMP-3 inhibited FAS shedding, this did not increase total surface levels of FAS but instead increased FAS levels within localised regions at the cell surface. A Disintegrin And Metalloproteinase 17 (ADAM17) is inhibited by TIMP-3 and depletion of ADAM17 with shRNA significantly decreased FAS shedding. However ADAM17 depletion did not induce apoptosis or replicate the effects of TIMP-3 by increasing localised clustering of cell surface FAS. ADAM17-depleted cells could activate caspase-3 when expressing levels of TIMP-3 that were otherwise sub-apoptotic, suggesting a partial role for ADAM17 mediated ectodomain shedding in TIMP-3 mediated apoptosis. We conclude that TIMP-3 induced apoptosis in VSMCs is highly dependent on FAS and is associated with changes in FAS and c-FLIP localisation, but is not solely dependent on shedding of the FAS ectodomain.

Dataset Information

The effect of resveratrol on expression of matrix metalloproteinase 9 and its tissue inhibitors in vascular smooth muscle cells.

Publications

The effect of resveratrol on expression of matrix metalloproteinase 9 and its tissue inhibitors in vascular smooth muscle cells.

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