Cho, Hyunju Lee, Ho-Youl Ahn, Dae-Ro Kim, Sang Yoon Kim, Sunyun Lee, Keun Byeol Lee, You Mie Park, Hyunsung Yang, Eun Gyeong 2024-01-20T23:03:15Z 2024-01-20T23:03:15Z 2021-09-03 2008-07 0026-895X https://pubs.kist.re.kr/handle/201004/133370 Targeting the oxygen-sensing mechanisms of the hypoxia-inducible factor (HIF) pathway provides pharmacological ways of manipulating the HIF response. Because HIF-1 alpha-specific prolyl-4 hydroxylases (PHDs) prime degradation of HIF-1 alpha, we have made an effort to find a small molecule capable of up-regulating the HIF pathway by inhibiting prolyl hydroxylation. Through an in vitro high-throughput screen, we have discovered a PHD2 inhibitor baicalein, which is also found to abrogate asparaginyl hydroxylation of HIF-1 alpha. Such inhibitory effects are reversed by the addition of excess 2-oxoglutarate and iron(II), suggesting the involvement of baicalein's binding at the enzyme active sites, which has also been corroborated by spectroscopic binding assays between baicalein and enzyme. In addition, baicalein suppresses ubiquitination of HIF-1 alpha, which works in concert with the inhibition of the HIF-specific hydroxylases to increase the HIF-1 alpha content, leading to induction of HIF-1-mediated reporter gene activity and target gene transcription in tissue culture cells, whereas it induces HIF-independent activation of other genes. Furthermore, in vivo organ models based on the chick chorioallantoic membrane assay demonstrate that baicalein promotes new blood vessel formation. Together, our results indicate that baicalein possesses a proangiogenic potential and thus might have the therapeutic utility in the treatment of ischemic diseases. English AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS HYPOXIA-INDUCIBLE FACTOR ENDOTHELIAL GROWTH-FACTOR PROLYL HYDROXYLASE SCUTELLARIA-BAICALENSIS CELL PROLIFERATION RESPONSE PATHWAY CANCER CELLS HIF INHIBITION HIF-1-ALPHA Baicalein induces functional hypoxia-inducible factor-1 alpha and angiogenesis Article 10.1124/mol.107.040162 1 MOLECULAR PHARMACOLOGY, v.74, no.1, pp.70 - 81 MOLECULAR PHARMACOLOGY 74 1 70 81 scie scopus 000256889600008 2-s2.0-45749108208 Pharmacology & Pharmacy Pharmacology & Pharmacy Article HYPOXIA-INDUCIBLE FACTOR ENDOTHELIAL GROWTH-FACTOR PROLYL HYDROXYLASE SCUTELLARIA-BAICALENSIS CELL PROLIFERATION RESPONSE PATHWAY CANCER CELLS HIF INHIBITION HIF-1-ALPHA baicalein hypoxia angiogenesis HIF prolyl hydroxylase