15-PGDH/15-KETE在缺氧性肺血管内皮细胞增殖，血管新生中的作用及机制的研究

Pulmonary arterial hypertension is a malignant cardiovascular disease which mechanism is complicated and still unknown. Our studies discovered that 15-HETE was involved in the hypoxia induced pulmonary arterial hypertension. However 15-HETE is rather instable with a very short lifespan,suggesting that the effects of 15-HETE may be mediated by its metabolic products.These as well as our preliminery studies showing that hypoxia increased 15-PGDH expression and the concentration of 15-KETE，an intermediary metabobolite of 15-PGDH,make us to believe that 15-PGDH/15-KETE play a role in the hypoxia induced pulmonary arterial hypertension. To teat the hypothesis we have proposed several experiments using animal models in hypoxia，immunohistory, HPLC/MS，pulmonary artery endothelial cells migration and tube formation, Co-Immunoprecipitation, ChIP and dual-luciferase reporter gene assay. Our sepcific aims: To examine the influence of hypoxia on the expression of 15-PGDH and production of 15-KETE; To determine the role of 15-PGDH/15-KETE in pulmonary arterial endothelial cell proliferation, migration and angiogenesis under hypoxic condition; To identify signal transduction pathways and network of protein-protein interaction that involved in 15-KETE induced pulmonary artery endothelial cell angiogenesis. The demonstration of the role of 15-PGDH/15-KETE in hypoxic induced PA remodeling and underlying the molecular mechanisms of the effects should have a profund impact on the identification of therapeutical targets for the treatment of pulmonary hypertension.

肺动脉高压是病因未明的心血管疾病，缺氧是重要诱因。我们证明15-LO/15-HETE与缺氧性肺动脉高压有关；但15-HETE稳定性差，可被15-PGDH代谢；缺氧通过上调15-PGDH/15-KETE抑制肺血管内皮凋亡，提示缺氧通过15-PGDH/15-KETE促进肺血管内皮增殖和重构。拟通过缺氧动物模型，组化，HPLC/MS，内皮细胞划痕和管腔形成，免疫共沉淀，染色质免疫共沉淀，双荧光素酶报告基因等证实该假设。本研究通过研究：缺氧对15-KETE及15-PGDH的影响；15-PGDH/15-KETE在缺氧性肺血管内皮增殖和血管新生中的作用；参与15-PGDH/15-KETE调控内皮细胞增殖的信号转导系统,及蛋白质相互作用网络，明确15-PGDH/15-KETE在缺氧性肺血管重构中的作用，阐明该作用的分子机制，进而揭示缺氧性肺血管重构的可能机理，为开发肺动脉高压药物提供潜在靶点。

《15-PGDH/15-KETE在缺氧性肺血管内皮细胞增殖，血管新生中的作用及机制的研究》课题获得国家自然科学基金资助，课题负责人朱大岭。现已达到研究预期目标。全部研究内容已全部完成，发表13篇文章，均发表在国外有影响的杂志上。本课题研究发现1. 缺氧可上调肺血管及细胞中15-KETE及15-PGDH的含量；2.缺氧可通过15-PGDH/15-KETE调控肺动脉内皮细胞及平滑肌细胞的增殖；3.ERK及PAR-2通路参与15-PGDH/15-KETE调控内皮及平滑肌细胞增殖的过程。本课题研究结果支持研究假设—15-PGDH/15-KETE参与缺氧引起的内皮细胞增殖和肺血管重构，为揭示肺动脉高压的发病及治疗提供理论依据。