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Nectandrin B Activates Endothelial Nitric-Oxide Synthase Phosphorylation in Endothelial Cells Role of the AMP-Activated Protein Kinase/Estrogen Receptor alpha/Phosphatidylinositol 3-kinase/Akt Pathway



Nectandrin B Activates Endothelial Nitric-Oxide Synthase Phosphorylation in Endothelial Cells Role of the AMP-Activated Protein Kinase/Estrogen Receptor alpha/Phosphatidylinositol 3-kinase/Akt Pathway







We revealed previously that nectandrin B isolated from Myristica fragrans (nutmeg, Myristicaceae) functions as a potent AMP-activated protein kinase (AMPK) activator and showed its antiobesity effect. In this study, we investigated whether nectandrin B affects phosphorylation of endothelial nitric-oxide synthase (eNOS) in human endothelial cells. Nectandrin B increased the phosphorylation of eNOS and nitric oxide (NO) production in a concentration-dependent manner and maximal effect was found at 1 μg/ml. Nectandrin B activates AMPK, presumably via Ca2+/calmodulin kinase II activation and nectandrin B-stimulated eNOS phosphorylation was reversed by AMPK inhibition. Both the enzyme activity of phosphatidylinositol 3-kinase (PI3K) and the estrogen receptor (ER)-dependent reporter gene transcription were enhanced by nectandrin B. ERα inhibition by specific antagonist or small interfering siRNA (siRNA) suppressed nectandrin B-mediated eNOS phosphorylation. Moreover, AMPK inhibition significantly reversed the activation of ER-dependent transcription and PI3K activation in response to nectandrin B. Nectandrin B evoked endothelium-dependent relaxation in rat aortic rings, and this was blocked by inhibition of AMPK, ER, or PI3K. These results suggest that potent AMPK activator nectandrin B enhances NO production via eNOS phosphorylation in endothelial cells and ERα-dependent PI3K activity is required.

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