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Nitric oxide (NO) produced by endothelial nitric-oxide synthase (eNOS) has antithrombotic and antiatherosclerotic properties in the vasculature. Previously, we demonstrated that saponins derived from the roots of Platycodon grandiflorum (CKS) inhibited the tumor necrosis factor-alpha-induced expression of adhesion molecules in human endothelial cells. In this study, we found that CKS increased eNOS phosphorylation and NO production in human endothelial cells. Treatment with CKS increased the phosphorylation of Akt, p38/MAPK, AMP-activated protein kinase (AMPK), and calmodulin-dependent protein kinase II (CaMK II) leading to increased NO production in human endothelial cells. Moreover, inhibitors of Akt (LY294002), p38/MAPK (SB203580), AMPK (compound C), and CaMK II (W7) failed to suppress CKS-induced eNOS phosphorylation. In addition, CKS-induced eNOS phosphorylation was inhibited by the overexpression of a dominant-negative mutant form of AMPK (DN-AMPK). Taken together, these results indicate that CKS stimulates eNOS phosphorylation and NO production via the activation of PI3K/Akt, p38/MAPK, AMPK, and CaMK II.

Original publication

DOI

10.1016/j.toxlet.2010.03.006

Type

Journal article

Journal

Toxicol Lett

Publication Date

02/06/2010

Volume

195

Pages

106 - 113

Keywords

AMP-Activated Protein Kinases, Endothelial Cells, Enzyme Activation, Humans, Nitric Oxide, Nitric Oxide Synthase Type III, Phosphorylation, Plant Extracts, Plant Roots, Platycodon, Proto-Oncogene Proteins c-akt, Saponins, p38 Mitogen-Activated Protein Kinases