Baicalein suppresses hypoxia-induced HIF-1alpha protein accumulation and activation through inhibition of reactive oxygen species and PI 3-kinase/Akt pathway in BV2 murine microglial cells.
Hypoxia induces an inflammatory activation of microglia during cerebral ischemia. The transcription factor of hypoxia-inducible genes hypoxia-inducible factor-1 (HIF-1) is known to be involved in inflammation and immune response. Although baicalein (BE), a flavonoid, is shown to have anti-inflammatory effects and attenuate ischemic injury, its action mechanism is not understood well. Thus, we examined effect of BE on hypoxia-induced HIF-1 activation and its signaling mechanism in BV2 microglial cells. BE inhibited hypoxia-induced HIF-1alpha protein accumulation and HIF-1 transcriptional activation. Consistently, BE suppressed hypoxia-induced expression of hypoxia responsive genes, iNOS, COX-2, and VEGF. We then showed that BE inhibited hypoxia-induced phosphorylation of Akt but not that of ERK and p38. Moreover, BE inhibited hypoxia-induced PI 3-kinase activation. Finally, we showed that BE inhibited hypoxia-induced ROS generation, and an antioxidant N-acetylcysteine reduced hypoxia-induced HIF-1alpha and iNOS protein expression and PI 3-kinase/Akt activation in BV2 microglia. Taken together, these results suggest that BE suppresses hypoxia-induced HIF-1alpha protein and activation as well as expression of hypoxia responsive genes by inhibiting ROS and PI 3-kinase/Akt pathway in BV2 microglia.
Hwang
Keun Young
KY
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Oh
Young Taek
YT
Yoon
Hana
H
Lee
Jinhwa
J
Kim
Hocheol
H
Choe
Wonchae
W
Kang
Insug
I
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004789:Enzyme Activation; D044950:Flavanones / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation
D044950:Flavanones; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; C006680:baicalein; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt