Polyphenols are common constituents in botanical extracts available in over-the-counter nutraceutical preparations as well as being found in different fruits and vegetables, olive oil, and beverages like red wine and tea. Based on a growing body of evidence it is thought that the chemoprotective effect of polyphenols involves the inhibition of reactive oxygen species (ROS) generation rather than simply scavenging the radicals. Recent studies indicate that NADPH oxidase is the major source of ROS in the three principal cell types of the blood vessel wall (e.g., endothelial cells (EC), vascular smooth muscle cells (VSMC), and adventitial fibroblasts). There has been growing interest in the vascular NADPH oxidases, largely because it is recognized that oxidative stress plays a critical role in the pathogenesis of vascular diseases, such as atherosclerosis. Preliminary studies performed in our group and others have demonstrated that ortho- methoxyphenols, such as apocynin, are activated by peroxidases in vivo and that their oxidation products appear to act as inhibitors of NADPH oxidase assembly and activation, although the exact identity of the oxidation products and the mechanism of inhibition have not been fully elucidated. Such information is critical for the ultimate development of safe and effective inhibitors of vascular NADPH oxidases. In the present application, we propose to obtain structural information on the active metabolites of apocynin-like compounds and the biochemical reactions by which they bind to and inhibit the assembly and activation of the NADPH oxidase complex. Specific goals of this R21 application are to: (1) Elucidate the chemical structures of the active metabolites of apocynin that bind to endothelial p47phox, p67phox, and p22phox peptide sequences and confirm that these compounds also bind to the same domains on the p47phox and p67phox protein subunits of NADPH oxidase; (2) Determine whether apocynin oxidation products disrupt specific protein-protein interactions that are involved in the assembly of mature NADPH oxidase. The outcome of these studies will be the foundation of a more detailed understanding of the chemical structure and molecular process by which apocynin-like compounds inhibit the assembly and activation of NADPH oxidase. ? ?
| Mora-Pale, Mauricio; Kwon, Seok Joon; Linhardt, Robert J et al. (2012) Trimer hydroxylated quinone derived from apocynin targets cysteine residues of p47phox preventing the activation of human vascular NADPH oxidase. Free Radic Biol Med 52:962-9 |
| Eker, Bilge; Zagorevski, Dmitri; Zhu, Guangyu et al. (2009) ENZYMATIC POLYMERIZATION OF PHENOLS IN ROOM TEMPERATURE IONIC LIQUIDS. J Mol Catal B Enzym 59:177-184 |
| Mora-Pale, Mauricio; Weïwer, Michel; Yu, Jingjing et al. (2009) Inhibition of human vascular NADPH oxidase by apocynin derived oligophenols. Bioorg Med Chem 17:5146-52 |
| Yu, Jingjing; Weiwer, Michel; Linhardt, Robert J et al. (2008) The role of the methoxyphenol apocynin, a vascular NADPH oxidase inhibitor, as a chemopreventative agent in the potential treatment of cardiovascular diseases. Curr Vasc Pharmacol 6:204-17 |
