脑缺血缺氧的病理生理及研究进展.pptVIP

* * * * 炎症反应加剧 细胞内钙超载 【发病机制】（Pathogenesis） 自由基生成增多 高能磷酸化合物缺乏 低氧诱导因子的作用 1．氧化磷酸化脱偶联 再灌注 线粒体损伤 氧化磷酸化脱偶联 ATP↓ 2．高能磷酸化合物缺乏 再灌注 腺苷、肌苷、次黄嘌呤等被冲掉 高能磷酸化合物的底物↓ 高能磷酸化合物缺乏 (lack of high-energy phosphate compound) Ca2+ * 一系列生化改变 缺血/缺氧 细胞能量储备耗竭 Na+/K+泵衰竭 酸中毒 细胞膜去极化 电压控制钙通道开放 谷氨酸释放 细胞内Ca2+浓度升高 激活 脂酶 ΔNMDA，AMPA及代谢性受体激活 NO合成酶 NO 自由基生成 蛋白酶 核酸内切酶 细胞死亡 再灌注 A＝ B ＝C ＝D 图例: A: 钙离子拮抗剂 B: 谷氨酸释放抑制剂 C :NMDA及非NMDA受体拮抗剂 D: 自由基清除剂 炎症 炎症反应加剧 细胞内钙超载 【发病机制】（Pathogenesis） 自由基生成增多 高能磷酸化合物缺乏 低氧诱导因子的作用 低氧诱导因子的作用(role of hypoxia-inducibe factor) Before HIF-1 was found, HRE had been identified in the 3′-enhancer region of the erythropoietin gene, whose transcription is up-regulated by more than 100-fold by severe hypoxia. Semenza and Wang defined a binding site critical for the hypoxia-inducible function, which involves a transcription factor induced by hypoxia. DISCOVERY OF HIF-1 STRUCTURE OF HIF-1 Fig. 2. Structures of the Hif1 gene and HIF-1 protein. The Hif1 gene is composed of 15 exons and 14 introns. HIF-1 protein possesses a basic helix-loop-helix (bHLH) and a PER-ARNT-SIM (PAS) domain, which are involved in HRE-binding and dimerization with ARNT. Its C-terminal contains two transacting domains (TAD) and a nuclear localization signal (NLS). The oxygen-dependent degradation domain (ODDD) contains two proline residues (P402 and P564), targeted by prolyl hydroxylases, and a lysine residue (K532), targeted by ARD1 acetyl transferase. Correlated background HIF-1 (hypoxia-inducible factor-1) pVHL (von Hippel-Lindau) EGLN (Egl-nine: egg laying nine) Semenza and Wang (1992) identified originally HIF-1 by its binding to a hypoxia response element in the human (EPO) gene. Maxwell et al. (1999) were the first to show that ubiquitination and proteasomal degradation of HIF-1α requires the pVHL, the substrate recognition subunit for an E3 ubiquitin ligase. Ivan et al. and