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Deprecated: Implicit conversion from float 298.79999999999995 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Environ+Toxicol 2017 ; 32 (3): 918-930 Nephropedia Template TP
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Andrographolide inhibits hypoxia-induced HIF-1alpha-driven endothelin 1 secretion by activating Nrf2/HO-1 and promoting the expression of prolyl hydroxylases 2/3 in human endothelial cells #MMPMID27297870
Lin HC; Su SL; Lu CY; Lin AH; Lin WC; Liu CS; Yang YC; Wang HM; Lii CK; Chen HW
Environ Toxicol 2017[Mar]; 32 (3): 918-930 PMID27297870show ga
Andrographolide, the main bioactive component of the medicinal plant Andrographis paniculata, has been shown to possess potent anti-inflammatory activity. Endothelin 1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, displays proinflammatory property. Hypoxia-inducible factor 1alpha (HIF-1alpha), the regulatory member of the transcription factor heterodimer HIF-1alpha/beta, is one of the most important molecules that responds to hypoxia. Changes in cellular HIF-1alpha protein level are the result of altered gene transcription and protein stability, with the latter being dependent on prolyl hydroxylases (PHDs). In this study, inhibition of pro-inflammatory ET-1 expression and changes of HIF-1alpha gene transcription and protein stability under hypoxia by andrographolide in EA.hy926 endothelial-like cells were investigated. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl(2.) We found that hypoxia stimulated the production of reactive oxygen species (ROS), the expression of HIF-1alpha mRNA and protein, and the expression and secretion of ET-1. These effects, however, were attenuated by co-exposure to andrographolide, bilirubin, and RuCO. Silencing Nrf2 and heme oxygenase 1 (HO-1) reversed the inhibitory effects of andrographolide on hypxoia-induced HIF-1alpha mRNA and protein expression. Moreover, andrographolide increased the expression of prolyl hydroxylases (PHD) 2/3, which hydroxylate HIF-1alpha and promotes HIF-1alpha proteasome degradation, with an increase in HIF-1alpha hydroxylation was noted under hypoxia. Inhibition of p38 MAPK abrogated the hypoxia-induced increases in HIF-1alpha mRNA and protein expression as well as ET-1 mRNA expression and secretion. Taken together, these results suggest that andrographolide suppresses hypoxia-induced pro-inflammatory ET-1 expression by activating Nrf2/HO-1, inhibiting p38 MAPK signaling, and promoting PHD2/3 expression. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 918-930, 2017.