15-KETE致大鼠缺氧性肺血管收缩的离子通道机理

发布时间：2018-09-05 10:21

【摘要】： HPV由Euler和Liljestrand于1946年首次提出,此后被广泛研究。但是其发生的确切机制至今尚不完全明了。目前认为内皮细胞衍生的血管活性物质在HPV中起重要的作用,并在在体HPV发生中是必须的,但很可能HPV的始发因素仍是PASMCs内部因素。我们前期的研究结果表明:慢性缺氧情况下,15-LO活性增强,从缺氧肺细胞浆转移至细胞膜,作用于AA,生成15-HETE、15-KETE等代谢产物,提示缺氧条件下15-LO的花生四烯酸代谢产物有其相应的细胞分布、细胞内定位及相应的作用位点。15-HETE以剂量依赖方式收缩PA环,缺氧的情况下尤为明显。由于15-HETE在动物体内不是AA的15-LO终产物,它可进一步代谢为15-KETE、8(S),15(S)-DiHETE等产物。通过对15-LO的花生四烯酸代谢产物对大鼠肺动脉作用的筛选,我们发现15-KETE具有强烈收缩大鼠肺动脉作用,以缺氧更明显。因此15-KETE在HPV中的作用有待于进一步研究。本文通过应用离体组织浴槽血管环实验技术、全细胞膜片钳技术、激光扫描共聚焦显微镜技术、Western Blot和RT-PCR技术、,从血管功能、电生理、蛋白质、mRNA水平上全面揭示15-KETE收缩大鼠肺动脉的离子通道机理。实验结果表明15-KETE以浓度依赖性的方式强烈收缩大鼠肺动脉,并且以缺氧组更显著。15-KETE抑制了大鼠PASMCs IKv,使大鼠PASMCs去极化,促进了细胞外液钙离子的内流,使大鼠PASMCs游离钙离子浓度增加,同时降低了Kv1.2、Kv1.5、Kv2.1、Kv3.4蛋白质和mRNA的表达,可能是介导缺氧与肺动脉收缩的一个新的重要因子。
[Abstract]:HPV was first proposed by Euler and Liljestrand in 1946 and has been extensively studied since then. However, the exact mechanism of its occurrence has not been fully understood. It is believed that vasoactive substances derived from endothelial cells play an important role in HPV and are necessary in the pathogenesis of HPV in vivo, but it is very likely that the origin of HPV is still an internal factor of PASMCs. Our previous research results showed that the activity of 15-LO was increased under chronic hypoxia, which was transferred from hypoxic lung cytoplasm to cell membrane, acting on the production of 15-HETE15-KETE and other metabolites by AA,. The results suggest that the arachidonic acid metabolites of 15-LO have their corresponding cellular distribution under anoxic condition, and the intracellular localization and the corresponding action site. 15-HETE constricts the PA ring in a dose-dependent manner, especially in the case of hypoxia. Since 15-HETE is not the end product of 15-LO of AA in animals, it can be further metabolized as 15-KETE8 (S), 15 (S) -DiHETE and so on. By screening the effects of arachidonic acid metabolites of 15-LO on pulmonary arteries in rats, we found that 15-KETE has a strong contractile effect on pulmonary arteries in rats, especially in hypoxia. Therefore, the role of 15-KETE in HPV needs further study. In this paper, by using in vitro tissue bath vessel ring experiment, whole-cell patch clamp technique, laser scanning confocal microscopy (LSCM), Western Blot and RT-PCR techniques, vascular function, electrophysiology, and electrophysiology were studied. The mechanism of ion channel in pulmonary artery induced by 15-KETE contraction in rats was fully revealed at the protein mRNA level. The results showed that 15-KETE strongly contracted the pulmonary artery in a concentration-dependent manner, and the hypoxia group inhibited the depolarization of rat PASMCs induced by PASMCs IKv, and promoted the influx of calcium ions in extracellular fluid. It may be a new important factor to mediate hypoxia and pulmonary artery contraction by increasing the concentration of free calcium ion of PASMCs and decreasing the expression of Kv1.2,Kv1.5,Kv2.1,Kv3.4 protein and mRNA.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2007
【分类号】：R363

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