Abstract
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.
Highlights
Oxidative stress plays a critical role in the pathogenesis of many cardiovascular diseases, including atherosclerosis, and is an attractive therapeutic target for cardiovascular diseases
We investigated the effects of xyloketal B on the heme oxygenase-1 (HO-1) gene induction and signaling pathways involved in xyloketal B-induced HO-1 expression in human umbilical vein endothelial cells (HUVECs) in vitro, as well as its effects on NADPH oxidase activity in zebrafish embryos in vivo
By using the similar culture system, we have shown that xyloketal B has no toxic effects on HUVECs in concentrations up to 160 μM by MTT assay
Summary
Oxidative stress plays a critical role in the pathogenesis of many cardiovascular diseases, including atherosclerosis, and is an attractive therapeutic target for cardiovascular diseases. Many antioxidant compounds have been developed for the treatment of cardiovascular diseases. Ebselen, a seleno-organic compound, has demonstrated its clinical efficacy and has been approved for clinical use in different countries, including Japan and China [1,2]. Xyloketal B might be a good candidate for further development as an antioxidant medicine in cardiovascular diseases. The relatively weak direct scavenging activity of xyloketal B cannot fully explain its potent antioxidant action [6]. In addition to direct antioxidant action (scavenging reactive oxygen species [ROS]/reactive nitrogen species [RNS]), many antioxidant compounds exert their antioxidant effects by activating the endogenous antioxidant defense system. We hypothesized that xyloketal B may protect against oxidant insults via modulating the endogenous antioxidant system
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