Tannin 1-α-O-galloylpunicalagin induces the calcium-dependent activation of endothelial nitric-oxide synthase via the phosphatidylinositol 3-kinase/Akt pathway in endothelial cells
2008
Chen, Lih-Geeng | Liu, Yen-Chin | Hsieh, Chia-Wen | Liao, Being-Chyuan | Wung, Being-Sun
Many polyphenols have been found to increase endothelial nitric oxide (NO) production. In our present study, we investigated the effects of 1-α-O-galloylpunicalagin upon endothelial nitric oxide synthase (eNOS) activity in endothelial cells (ECs). Both 1-α-O-galloylpunicalagin and punicalagin induced NO production in a dose-dependent manner in ECs. Despite having similar chemical structures, punicalagin induced lower levels of NO production than 1-α-O-galloylpunicalagin. After 1-α-O-galloylpunicalagin addition, a rise in the intracellular Ca²⁺ concentration preceded NO production. The Ca²⁺ ionophore A23187 stimulated eNOS phosphorylation and augmented NO production. Pretreatment with Ca²⁺ chelators inhibited 1-α-O-galloylpunicalagin-induced eNOS phosphorylation and NO production. Treatment with 1-α-O-galloylpunicalagin did not alter the eNOS protein levels but, unlike punicalagin, induced a sustained activation of eNOS Ser¹¹⁷⁹ phosphorylation. 1-α-O-galloylpunicalagin was also found to activate ERK1/2, JNK and Akt in ECs. Moreover, simultaneous treatment of these cells with specific phosphatidylinositol-3-kinase inhibitors significantly inhibited the observed increases in eNOS activity and phosphorylation levels. In contrast, the inhibition of (ERK)1/2, JNK and p38 had no influence on eNOS Ser¹¹⁷⁹ phosphorylation. Our present results thus indicate that the 1-α-O-galloylpunicalagin-induced calcium-dependent activation of eNOS is primarily mediated via a phosphatidylinositol 3-kinase/Akt-dependent increase in eNOS activity, and occurs independently of the eNOS protein content.
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