Intermedin调节低氧性肺血管改建的作用及分子机制

项目名称： Intermedin调节低氧性肺血管改建的作用及分子机制

项目编号： No.30871031

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 龚永生

作者单位： 温州医科大学

项目金额： 29万元

中文摘要： 本课题旨在研究新发现的小分子活性肽intermedin(IMD)对低氧性肺动脉高压和肺血管改建的防治作用，并探讨IMD的效应与一氧化氮（NO）途径和调节凋亡是否有关。主要内容与结果： 1、在整体动物模型上，观察了IMD对大鼠慢性低氧性肺动脉高压的作用，并初步探讨其机制。结果表明：IMD有明显防止低氧大鼠肺动脉压升高、右心室肥大与肺小动脉改建的作用；其效应部分与改善NO合酶活性、提高肺动脉L-精氨酸的转运，从而提高NO的含量有关；且IMD可通过激活内质网途径、上调caspase-12、GRP78/GRP94的表达而促进肺组织的细胞凋亡。 2、研究了IMD对离体肺动脉环舒缩功能的影响及其机制。发现IMD对大鼠离体肺动脉环具有浓度依赖性的舒张作用且呈内皮依赖性，该作用可能与NO途径、KATP通道和前列腺环素途径有关，而与钙离子通道无关。 3、在低氧培养的肺动脉平滑肌细胞、肺血管内皮细胞上，进一步探讨了IMD对细胞增殖与凋亡的作用与机制。结果显示：对于平滑肌细胞，IMD有促进凋亡和抑制增殖的作用，但内质网途径可能不是主要的途径。对于内皮细胞，IMD有抑制凋亡的作用，且与内质网途径的激活有关。

中文关键词： intermedin；低氧;高血压;肺性；凋亡；一氧化氮

英文摘要： The present study was designed to determine the prevention and treatment of intermedin (IMD), a novel micromolecular bioactive peptide, in rats with chronic hypoxic pulmonary hypertension, and explore whether the effectiveness of IMD is associated with nitric oxide (NO) pathway and apoptosis. The following is the main results . ⑴he rat models of chronic hypoxic pulmonary hypertension were established to investigate the effectiveness and mechanism of IMD. Our results suggest that IMD has a prophylactic effect against hypoxic pulmonary hypertension in rats, and the mechanism of this effect is possibly associated with the increase of the content of NO by raising increasing the activity of NOS and promoting L-Arg transport; and IMD could improve apoptosis of pulmonary artery smooth muscle cells by activating the endoplasmic reticulum stress pathway and up-regulating the expression of caspase-12 and GRP78/GRP94. ⑵he vasorelaxant effect and mechanism of IMD on isolated pulmonary arterial rings of rats in vitro were also explored. Our results suggest that IMD can induce a significant concentration-dependent relaxation and endothelium dependent manner in rat pulmonary arterial rings. The mechanism is possibly mediated by NO pathway, KATP channel and prostacyclin pathway, while Ca2+ channel may not take part in the relaxation effect of IMD in rat main pulmonary artery. ⑶he pulmonary artery smooth muscle cells and pulmonary vascular endothelial cells after exposed to hypoxia were cultured in vitro to evaluate the role of IMD on proliferation and apoptosis. Our results suggest that IMD can improve apoptosis and inhibit proliferation in pulmonary artery smooth muscle cells, while the endoplasmic reticulum stress pathway may not be a mainly signaling pathway. IMD can improve apoptosis in pulmonary vascular endothelial cells through endoplasmic reticulum stress pathway.

英文关键词： Intermedin; Hypoxia; Hypertension; pulmonary; Apoptosis; Nitric oxide