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Vascul Pharmacol. 2007 Feb;46(2):114-21. Epub 2006 Sep 3.

Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma.

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Department of Cardiology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.


The effect of resveratrol on macrophage EMMPRIN expression and its potential mechanism was investigated. Both EMMPRIN expression and MMP-9 activity, respectively assayed by Western blot and zymography, were greatly up-regulated during PMA-induced macrophage differentiation from THP-1 monocytes. Both resveratrol and a PPARgamma agonist, pioglitazone, significantly inhibited EMMPRIN expression and MMP-9 activity in a concentration-dependent manner. The effects of pioglitazone and resveratrol were reversed by pretreatment of THP-1 cells with a PPARgamma antagonist, GW9662, prior to PMA induction. Thus, data suggest that resveratrol may down-regulate EMMPRIN and MMP-9 through PPARgamma activation. This possibility was further examined in resveratrol-or pioglitazone-treated U937 cells, which had been co-transfected with a PPARgamma expression vector and a luciferase reporter vector containing three tandem repeats of PPRE in cis. Results of the agonist-activated luciferase assay showed that resveratrol activated PPARgamma in a concentration-dependent manner. Since EMMPRIN and MMP-9 up-regulation is associated with activation of the NF-kappaB pathway, we investigated the effect of pioglitazone and resveratrol on TNF-alpha-induced NF-kappaB activation. Western blot results indicated that both pioglitazone and resveratrol markedly inhibited the NF-kappaB pathway through suppressing IkappaB protein phosphorylation in macrophages, although this effect of resveratrol was not reversed by GW9662. In conclusion, resveratrol can down-regulate EMMPRIN expression by macrophages via activating PPARgamma. This may be a primary mechanism of its inhibitory effect on MMP-9.

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