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ARS Home » Midwest Area » Madison, Wisconsin » Cereal Crops Research » Research » Publications at this Location » Publication #312464
Title: Oat avenanthramides induce heme oxygenase-1 expression via Nrf2-mediated signaling in HK-2 cells

Author
item FU, JUNSHENG - North Carolina Agricultural And Technical State University
item ZHU, YINGDONG - North Carolina Agricultural And Technical State University
item YERKE, AARON - North Carolina Agricultural And Technical State University
item Wise, Mitchell
item JOHNSON, JODEE - Quaker Oats
item CHU, YIFANG - Quaker Oats
item SANG, SHENGMIN - North Carolina Agricultural And Technical State University

Submitted to: Molecular Nutrition and Food Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/17/2015
Publication Date: 12/2/2015
Citation: Fu, J., Zhu, Y., Yerke, A., Wise, M.L., Johnson, J., Chu, Y., Sang, S. 2015. Oat avenanthramides induce heme oxygenase-1 expression via Nrf2-mediated signaling in HK-2 cells. Molecular Nutrition and Food Research. 59:2471-2479.

Interpretive Summary: Avenanthramides are phenolic compounds found, among food crops, uniquely in oats. These metabolites have demonstrated antioxidant properties and, in cellular assays, they inhibit certain biomarkers for atherosclerosis. Avenanthramides also appear to up-regulate several key antioxidant enzyme systems in animal studies as well as in humans. This report describes the ability of the three main avenanthramide congeners found in oat grain, 2c, 2f and 2p, to up-regulate heme oxygenase-1 (HO-1) biosynthesis in HK-2 cell cultures. HO-1 is an essential defense mechanism to protect cells from oxidative stress. Production of this enzyme is regulated primarily through binding of a transcription factor termed Nrf-2 to a DNA sequence called the antioxidant response element (ARE). Nrf-2 binding to ARE is a regulatory mechanism involved in several mammalian antioxidant systems. Results from these experiments clearly show that all three of the avenanthramides similarly increased expression of HO-1 and that Nrf-2 was translocated into the nucleus of the cells. Chemical modification of the avenanthramides (reduction of a double bond) completely abrogated their ability to activate the Nrf-2/ARE signaling. Introduction of a reactive oxygen scavenger (N-acetyl cysteine) into the culture media significantly reduced the level of HO-1 expression. Thus, expression of HO-1 in the HK-2 cell line is up-regulated by both reactive oxygen and avenanthramides. The impact of this report is to demonstrate that the avenanthramides activate HO-1 expression through the Nrf-2/ARE signaling pathway, a mechanism that has been observed with other phytonutrients. These findings have implications for the antioxidant response to avenanthramide supplementation observed in animal studies and point to additional nutritional benefits associated with oat consumption.

Technical Abstract: Numerous laboratory and human studies have shown that avenanthramides (AVAs), unique compounds found in oats, are strong antioxidants. Their underlying mechanisms, however, remain unclear. We demonstrated for the first time that the three major AVAs in oats—2c, 2f, and 2p—significantly increased heme oxygenase-1 (HO-1) expression in HK-2 cells in both a dose- and time-dependent manner. Furthermore, mechanistic studies revealed that HO-1 expression induced by AVAs is mediated via Nrf2 translocation. The addition of N-acetylcysteine (NAC) suppressed the HO-1 expression induced by 2c, 2f, and 2p, establishing that ROS plays an important role on the up-regulation of HO-1 by AVAs. All three AVAs stimulated Nrf2 nuclear translocation in both a dose- and time-dependent manner. However, pretreatment of cells with specific inhibitors of p38 (SB202190), pI3K (LY294002), and MEK1 (PD098059) did not attenuate AVA-induced HO-1 expression, suggesting that HO-1 expression is not associated with PI3K or MAPK activation. Moreover, hydrogenation of the double bond of the functional a,ß-unsaturated carbonyl group of AVAs eliminated their effects on HO-1 expression, suggesting a critical role for the functional a,ß-unsaturated carbonyl group in the mechanism of action of AVAs.