MuRF1在低氧性肺动脉高压中的作用及机制

张婧; 文新元; 韦红梅; 薛茜茜; 金玲; 杨自更; 吴宾

doi:10.12125/j.chj.202302060

MuRF1在低氧性肺动脉高压中的作用及机制

Effects of MuRF1 on hypoxia-induced pulmonary hypertension in mice and underlying mechanism

摘要

摘要:
目的探讨肌肉环指蛋白1（MuRF1）在低氧性肺动脉高压（HPH）中的作用及可能机制。
方法将MuRF1转基因敲除小鼠（MuRF1 KO）及其同窝野生型（WT）小鼠随机分到对照（nWT）组、对照+HPH（hWT）组、MuRF1 KO（nMuRF1-KO）组、MuRF1 KO+HPH（hMuRF1-KO）组。其中，hWT组和hMuRF1-KO组置于低压低氧人工实验舱内，nWT组和nMuRF1-KO组置于常压常氧SPF环境中，维持28 d。检测小鼠右心功能及右心室重塑水平、远端肺小动脉血管重塑水平、肺泡灌洗液炎症因子表达、MuRF1和大电导钙激活钾通道β1亚基（BK-β1）蛋白表达。
结果与nWT组相比， hWT组右室内径（RVID）显著降低（P<0.01），右室前壁厚度（RVAW）、右心室收缩压（RVSP）、右心室肥厚指数（RVHI）、胶原容积分数（CVF）显著增加（P<0.01），远端肺动脉壁厚度比（WT%）、肺动脉壁面积比（WA%）、肺动脉肌化水平、相对肺重量显著增加（P<0.01），肺泡灌洗液中炎症因子IL-1β、IL-6、TNF-α显著增加（P<0.01），MuRF1表达显著增加（P<0.05），BK-β1表达降低（P<0.05）。与hWT组相比，hMuRF1-KO组RVID显著增加（P<0.05），RVAW、RVSP、RVHI、CVF显著降低（P<0.05），WT%、WA%、肺动脉肌化水平、相对肺重量显著降低（P<0.05，P<0.01），肺泡灌洗液中炎症因子IL-1β、IL-6、TNF-α也显著减少（P<0.05，P<0.01），BK-β1表达显著增加（P<0.05）。
结论敲除MuRF1可改善HPH小鼠右心功能障碍和右室重塑，减轻肺血管重塑和肺血管炎性环境，其机制可能与敲除MuRF1抑制BK-β1降解有关。

Abstract:
AIM To explore the effect of MuRF1 on hypoxia-induced pulmonary hypertension (HPH) and its underlying mechanism.
METHODS MuRF1 knockout (KO) mice and their wild type (WT) littermates were randomly allocated to 4 groups: WT group (nWT), WT+HPH group (hWT), KO group (nMuRF1-KO) and KO+HPH group (hMuRF1-KO). hWT group and hMuRF1-KO group were placed in low-pressure and low-oxygen artificial experimental chamber, and nWT group and nMuRF1-KO group were placed in atmospheric oxygen SPF environment for 28 days. The cardiac function and the remodeling level of right ventricle, the remodeling level of distal pulmonary artery, the expression of inflammatory factors in bronchoalveolar lavage fluid (BALF) and the expression levels of MuRF1 and BK-β1 were determined in mice.
RESULTS Compared with those in nWT group, RVID was significantly decreased (P<0.01), with up-regulated RVAW, RVSP, RVHI and CVF (P<0.01), and enhanced WT%, WA%, distal pulmonary artery muscularization, relative lung weight and the levels of IL-1β, IL-6, TNF-α in BALF (P<0.01), as well as increased MuRF1 (P<0.05) and decreased BK-β1 (P<0.05) expression in the lung tissue in hWT group. Compared with those in hWT group, RVID was significantly increased (P<0.05), with down-regulated RVAW, RVSP, RVHI and CVF (P<0.05), and decreased WT%, WA%, distal pulmonary artery muscularization and relative lung weight and the levels of IL-1β, IL-6, TNF-α in BALF (P<0.05, P<0.01), as well as decreased MuRF1 (P<0.01) and increased BK-β1 expression (P<0.05) in the lung tissue in hMuRF1-KO group.
CONCLUSION MuRF1 knockout improves right ventricular dysfunction and right ventricular remodeling, and alleviates pulmonary vascular remodeling and inflammatory environment of pulmonary vessels in HPH mice, which may be related to the inhibition of BK-β1 degradation by MuRF1 knockout.

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