Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish

• Published in: Marine drugs Vol. 11; no. 2; pp. 504 - 522
• Main Authors: Li, Zhen-Xing, Chen, Jian-Wen, Yuan, Feng, Huang, Yun-Ying, Zhao, Li-Yan, Li, Jie, Su, Huan-Xing, Liu, Jie, Pang, Ji-Yan, Lin, Yong-Cheng, Lu, Xi-Lin, Pei, Zhong, Wang, Guan-Lei, Guan, Yong-Yuan
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.02.2013; MDPI
• Subjects: Animals; Antioxidant Response Elements; apoptosis; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HO-1; Humans; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf-2; Protein Binding; Pyrans - chemistry; Pyrans - metabolism; Pyrans - pharmacology; reactive oxygen species; Respiratory Burst - drug effects; Respiratory Burst - physiology; Reverse Transcriptase Polymerase Chain Reaction; xyloketal B; Zebrafish
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md11020504

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B.