Experimental Biology 2010: Resveratrol Exhibits Anti-Atherogenic Properties By Facilitating Cholesterol Efflux From THP-1 Human Monocytes/macrophages

Purpose of Study: Resveratrol, a plant derived polyphenol found in red wine and grapes, exerts anti-inflammatory, antioxidant, and cardioprotective effects. We hypothesized that mechanisms underlying beneficial effects of resveratrol on atherosclerosis may involve prevention of cholesterol overload, limiting macrophage foam cell formation (FCF). This study examines the effect of resveratrol on expression of proteins involved in reverse cholesterol transport (RCT) out of the macrophage and on FCF in vitro.

Methods Used: THP-1 monocytes/macrophages, a pertinent model of atherosclerosis, were incubated ± resveratrol (50 µM, 24h) with/without addition of the inflammatory atherogenic cytokine interferon (IFN)-? (500 U/ml). Expression of the cholesterol-metabolizing enzyme P450 27-hydroxylase (27-OHase) and the ATP binding cassette transporter A1 (ABCA1) in THP-1 monocytes was assessed by quantitative real time RT-PCR. THP-1 differentiated macrophages (phorbol dibutyrate, 300nM, 48h) were exposed to acetylated LDL (50µg/ml, 48h) ± resveratrol and ± IFN-?. FCF of lipid-laden macrophages was quantified as percent oil red O stained cells by light microscopy. Studies were performed in triplicate.

Summary of Results: Resveratrol significantly increased 27-OHase and ABCA1 mRNA (mean±SEM, 246.2 ±20.4% of control, P<0.01 and 194.2 ±14.8% of control, P<0.01 respectively). Resveratrol negated the downregulation of 27-OHase by IFN-? (132.4 ±12.1% of control for resveratrol + IFN-? vs. 49.3 ±2.9% for IFN-? alone, P<0.01). Resveratrol also abolished IFN-?-induced suppression of ABCA1 (149.6 ±14.6% for resveratrol + IFN-? vs. 67.0 ±3.9% for IFN-? alone, P<0.01). THP-1 macrophages showed a significant decrease in FCF in the presence of resveratrol compared to control (22.70±3.05% vs. 35.67 ±3.06%, P<0.05). Resveratrol also reduced FCF initiated by IFN-? (44.67±4.16% for resveratrol + IFN-? vs. 73.67±7.77% for IFN-? alone, P<0.05).

Conclusions: 27-OHase and ABCA1, proteins involved in RCT away from atheroma, are critical regulators of macrophage cholesterol efflux. Demonstration of improved cholesterol homeostasis by resveratrol, even in an inflammatory milieu, provides evidence of a mechanism by which this natural compound may prevent atherosclerotic lesion formation leading to decreased cardiovascular events.