Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

Abstract

The development of choroidal neovascularization (CNV) is a critical step in the pathogenesis of age-related macular degeneration (AMD), a vision-threatening disease. In this study, we used a mouse model of AMD to study the protective effects of resveratrol (RSV) supplementation against CNV as well as the underlying molecular mechanisms. Mice were orally pretreated with RSV daily for 5 days. On the fifth day, the mice underwent laser photocoagulation to induce CNV. One week after laser treatment, CNV volume was significantly lower in the RSV-treated mice compared with vehicle-treated animals. In addition, RSV treatment significantly inhibited macrophage infiltration into the retinal pigment epithelium (RPE)-choroid and suppressed the expression of inflammatory and angiogenic molecules, including vascular endothelial growth factor, monocyte chemotactic protein-1 and intercellular adhesion molecule-1. Importantly, RSV prevented the CNV-induced decrease in activated AMP-activated protein kinase and increase in activated nuclear factor-κB in the RPE-choroid complex. The regulatory effects of RSV on these molecules were confirmed in RPE, microvascular endothelial and macrophage cell lines. Inhibition of macrophage infiltration by RSV was confirmed by in vitro scratch and migration assays. RSV suppressed CNV development, reducing the levels of multiple cytokines secreted from several cell types and inhibiting macrophage migration. The direct effects of RSV on each cell type were confirmed in vitro. Although further studies are needed, RSV could potentially be applied in the clinic to prevent CNV development in AMD.

Resveratrol attenuates ICAM-1 expression and monocyte adhesiveness to TNF-α-treated endothelial cells: evidence for an anti-inflammatory cascade mediated by the miR-221/222/AMPK/p38/NF-κB pathway

“…As AMPK is a target of resveratrol in several model systems181920, we investigated whether resveratrol could modulate the AMPK-mediated pathways that inhibit ICAM-1 expression. Compared with vehicle control-treated cells, significant AMPK activation was observed beginning at 5 min after resveratrol treatment and continuing for 15 min (Fig.…”

Resveratrol ameliorates high glucose-induced oxidative stress injury in human umbilical vein endothelial cells by activating AMPK

“…Here, we investigated the influence of resveratrol, a natural compound with beneficial effects in many disease models (Nagai et al, 2014, Rege et al, 2014, Saldanha et al, 2013, Zhu et al, 2014, on cell viability of HG-treated HUVECs. The anticipated HG-induced suppression of HUVEC viability was restored by treatment with resveratrol, indicating the protective potential of resveratrol in HG-induced vascular cell injury.…”

“…Although the effects of resveratrol have been linked to oxidative stress (Zhu et al , 2014) and AMPK signaling in many diseases (Lea et al , 2014, Nagai et al , 2014, the exact mechanisms by which it exerts these effects remain incompletely understood. Therefore, the aim of the present study was to investigate the effect of resveratrol on HG-induced vascular injury and clarify the mechanism underlying these effects.…”

SIRT1 mediated inhibition of VEGF/VEGFR2 signaling by Resveratrol and its relevance to choroidal neovascularization

“…Many of the activities of RSV are mediated through sirtuin1 (SIRT1), which in turn acts by deacetylation of transcription factors and other cellular proteins [6]. Recent reports have shown that RSV can suppress hypoxia-induced VEGF expression and secretion in an immortalized endothelial cell line derived from monkey retina/choroid [7], human adult RPE cells [8] and macrophages [9]. Furthermore, systemic application of RSV inhibits angiogenesis in murine CNV models [9, 10].…”