Baicalein induces functional hypoxia-inducible factor-1α and angiogenesis
Baicalein induces functional hypoxia-inducible factor-1α and angiogenesis
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DOI：
10.1124/mol.107.040162
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发表时间：
2008-07-01
影响因子：
3.6
通讯作者：
Yang, Eun Gyeong
中科院分区：
文献类型：
--
作者：
Cho, Hyunju;Lee, Ho-Youl;Yang, Eun Gyeong
靶向低氧诱导因子（HIF）通路的氧敏感机制提供了操纵HIF反应的药理学方法。由于HIF-1 α特异性脯氨酰-4羟化酶（PHD）引发HIF-1 α的降解，我们已经努力寻找能够通过抑制脯氨酰羟化来上调HIF途径的小分子。通过体外高通量筛选，我们发现了一种PHD 2抑制剂黄芩素，它也被发现可以消除HIF-1 α的天冬酰胺酰羟基化。这种抑制作用被逆转，通过添加过量的2-酮戊二酸和铁（II），表明黄芩素的结合在酶的活性位点，这也证实了黄芩素和酶之间的光谱结合测定的参与。此外，黄芩素抑制HIF-1 α的泛素化，其与HIF特异性羟化酶的抑制协同作用以增加HIF-1 α含量，导致诱导组织培养细胞中HIF-1介导的报告基因活性和靶基因转录，而黄芩素诱导其他基因的HIF非依赖性激活。此外，在体内器官模型的基础上，鸡绒毛尿囊膜试验表明，黄芩素促进新血管形成。总之，我们的研究结果表明，黄芩素具有促血管生成的潜力，因此可能有治疗缺血性疾病的治疗效用。
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.