Enterolactone induces heme oxygenase-1 expression through nuclear factor-E2-related factor 2 activation in endothelial cells.
Enterolactone is a lignan formed by enterobacteria from precursors in plant foods. Due to its phenolic structure, it can act as an antioxidant, e.g. via direct scavenging of hydroxyl radical. Moreover, many, but not all, phenolic compounds can have indirect antioxidative effects through induction of heme oxygenase-1 (HO-1), which has antiinflammatory functions via production of antioxidants bilirubin and biliverdin as well as carbon monoxide, thereby contributing to cardiovascular health. Our aim was therefore to assess whether enterolactone has indirect antioxidative effects via induction of HO-1 in endothelial cells. The effect of enterolactone on HO-1 mRNA and protein expression in human umbilical vein endothelial cells (HUVEC) was analyzed by quantitative real-time PCR and western blot. The role of nuclear factor-E2-related factor 2 (Nrf2) in HO-1 induction by enterolactone was studied using small interfering RNA (siRNA) and chromatin immunoprecipitation (ChIP) methods. Our results showed that enterolactone induced HO-1 in HUVEC in a time- and concentration-dependent manner. The induction appeared to be mediated via the transcription factor Nrf2, as Nrf2 siRNA abolished the HO-1 induction by enterolactone. We also showed using ChIP that exposure to enterolactone increased the binding of Nrf2 to the promoter region of HO-1. In conclusion, enterolactone increases the expression of HO-1 via Nrf2, which may contribute to its vasculoprotective effects.
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FIN-70211 Kuopio, Finland.
Annukka M
AM
Kivelä
Emilia
E
Kansanen
Henna-Kaisa
HK
Jyrkkänen
Tarja
T
Nurmi
Seppo
S
Ylä-Herttuala
Anna-Liisa
AL
Levonen
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D000975:Antioxidants; D017931:DNA Primers; D017705:Lignans; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1; D015107:4-Butyrolactone; C029497:2,3-bis(3'-hydroxybenzyl)butyrolactone