title: Role of Hydroxytyrosol-dependent Regulation of HO-1 Expression in Promoting Wound Healing of Vascular Endothelial Cells via Nrf2 De Novo Synthesis and Stabilization.
abstract: Hydroxytyrosol (HT), an olive plant (Olea europaea L.) polyphenol, has proven atheroprotective effects. We previously demonstrated that heme oxygenase-1 (HO-1) is involved in the HT dependent prevention of dysfunction induced by oxidative stress in vascular endothelial cells (VECs). Here, we further investigated the signaling pathway of HT-dependent HO-1 expression in VECs. HT dose- and time-dependently increased HO-1 mRNA and protein levels through the PI3K/Akt and ERK1/2 pathways. Cycloheximide and actinomycin D inhibited both increases, suggesting that HT-triggered HO-1 induction is transcriptionally regulated and that de novo protein synthesis is necessary for this HT effect. HT stimulated nuclear accumulation of nuclear factor E2-related factor 2 (Nrf2). This Nrf2 accumulation was blocked by actinomycin D and cycloheximide whereas HT in combination with the 26S proteasome inhibitor MG132 enhanced the accumulation. HT also extended the half-life of Nrf2 proteins by decelerating its turnover. Moreover, HO-1 inhibitor, ZnppIX and CO scavenger, hemoglobin impaired HT-dependent wound healing while CORM-2, a CO generator, accelerated wound closure. Together, these data demonstrate that HT upregulates HO-1 expression by stimulating the nuclear accumulation and stabilization of Nrf2, leading to the wound repair of VECs crucial in the prevention of atherosclerosis.
authors: Faculty of Life and Environment Sciences, University of Tsukuba, Ibaraki, 305-8572, Japan.
authors: Houda
authors: H
authors: Zrelli
authors: Faculty of Life and Environment Sciences, University of Tsukuba, Ibaraki, 305-8572, Japan.
authors: Miki
authors: M
authors: Kusunoki
authors: Faculty of Life and Environment Sciences, University of Tsukuba, Ibaraki, 305-8572, Japan.
authors: Hitoshi
authors: H
authors: Miyazaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D031658:Olea / Q000737:chemistry; D018384:Oxidative Stress; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D051267:NF-E2-Related Factor 2; C005975:3,4-dihydroxyphenylethanol; D051547:Heme Oxygenase-1; D010626:Phenylethyl Alcohol
keywords: atherosclerosis; heme oxygenase-1; hydroxytyrosol; nuclear factor-E2 regulated factor 2; vascular endothelial cells; wound healing