共同研究していた大阪医科大学の胸部外科の月山先生の論文がin pressになりました。
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AbstractCatechins have recently been reported to increase the cellular content of the hypoxia-inducible factor (HIF)-1α within mammalian cells. These catechins have a gallate moiety as a common structure. We now report that n-propyl gallate (nPG) also increases the HIF-1α protein in the rat heart-derived H9c2 cells. The increase was dose-dependent and reached a maximum at 2–4 h after the addition of nPG to the cells. nPG did not change the HIF-1α mRNA level, showing that the increase is a posttranscriptional event. Although nPG did not inhibit the HIF prolyl hydroxylase, gallate, the hydrolysis product of nPG, inhibited the enzyme completely at submillimolar concentrations. Model building studies on the human HIF prolyl hydroxylase 2 showed that the two phenolate oxygen atoms of gallate form a chelate with the active site Fe2+, while the carboxyl group of gallate forms a strong ionic/hydrogen bonding interaction with Arg383, explaining why nPG, which has an esterified carboxyl group, is unable to inhibit the hydroxylase. Together with the observation that gallate was detected in the H9c2 cells treated with nPG, these results suggest that nPG incorporated into the cells is hydrolyzed and the released gallate inhibits the HIF prolyl hydroxylase, thereby reducing the HIF degradation rate and increasing the HIF-1α content.
Keywords: Gallic acid; n-Propyl gallate; Hypoxia inducible factor; Prolyl hydroxylase; Chelation; Ferrous ion; Ubiquitin