PHB2抑制低氧性肺动脉高压小鼠右心室重塑的作用

Prohibitin 2 Inhibits Right Ventricular Remodeling in Mice with Hypoxia-induced Pulmonary Hypertension

目的:探讨抗增殖蛋白2(PHB2)在低氧性肺动脉高压(HPH)诱导的右心室重塑中的作用及可能机制。方法:将普通8周龄的C57BL/6小鼠随机分为:对照组(Control)、HPH组、HPH+空病毒(HPH+vector)组、HPH+过表达PHB2(HPH+PHB2)组。HPH组、HPH+空病毒组、HPH+过表达PHB2组置于低压低氧人工舱内维持4 w,对照组置于常压常氧环境中维持4 w。实验开始3 w前,尾静脉注射平滑肌特异性PHB2过表达的AAV9腺相关病毒及其对照病毒。评估小鼠右室血流动力学、右室重塑指标、炎症、氧化应激、血管活性物质水平以及肺组织PHB2和p-Stat3蛋白表达。结果:与对照组相比,HPH组和HPH+空病毒组RVSP、RVAW、RVHI显著增加(P<0.05),而RVID显著降低(P<0.05),右室CVF显著增加(P<0.05),血浆ET-1和BNP显著增加(P<0.05),血浆NO、总NOS和iNOS显著降低(P<0.05),右心IL-1β、IL-6及TNF-α显著增加(P<0.05),SOD和GSH-Px显著降低(P<0.05),肺组织PHB2表达降低(P<0.05),p-STAT3表达增加(P<0.05)。与HPH组和HPH+空病毒组相比,HPH+过表达PHB2组RVSP、RVAW、RVHI显著降低(P<0.05),而RVID显著增加(P<0.05),右室CVF显著降低(P<0.05),血浆ET-1和BNP显著降低(P<0.05),血浆NO、总NOS和iNOS显著增加(P<0.05),右心IL-1β、IL-6及TNF-α显著降低(P<0.05),SOD和GSH-Px显著增加(P<0.05),肺组织PHB2表达增加(P<0.05),p-STAT3表达降低(P<0.05)。结论:PHB2可减轻HPH诱发的右心室重塑,其机制可能与PHB2抑制STAT3的磷酸化水平有关。

Objective:To explore the effects of prohibitin 2 on right ventricular remodeling in hypoxia-induced pulmonary hypertension(HPH)mice and potential mechanisms.Methods:Eight-week-old male mice were randomly allocated to the following 4 groups:control group,HPH group,HPH+vector group and HPH+PHB2 group.HPH group,HPH+vector group and HPH+PHB2 group were placed in low-pressure and low-oxygen artificial chamber,and control group were placed in atmospheric oxygen environment for 4 weeks.Adeno-associated virus serotype 9(AAV9)carrying smooth muscle promoter-driven SM22ap encoding PHB2 and empty vectors were injected via tail vein 3 weeks prior to model construction.Hemodynamics,the level of right ventricle remodeling,inflammation,oxidative stress and vasoactive substances,and the expression levels of PHB2 and p-STAT3 were determined in mice.Results:Compared with control group,RVSP,RVAW,RVHI and CVP were increased significantly(P<0.05)and RVID was decreased in HPH group and HPH+vector group(P<0.05),with upregulated plasma ET-1 and BNP(P<0.05)and downregulated NO,t-NOS and iNOS(P<0.05),as well as increased IL-1β,IL-6 and TNF-αand decreased SOD and GSH-Px in right ventricular tissue(P<0.05),and the levels of PHB2 expression in the lung tissue were decreased(P<0.05)and p-STAT3 expression was increased(P<0.05)in HPH group and HPH+vector group.Compared with HPH group and HPH+vector group,RVSP,RVAW,RVHI and CVP were decreased significantly(P<0.05)and RVID was increased in HPH+PHB2 group(P<0.05),with downregulated plasma ET-1 and BNP and upregulated NO,t-NOS and iNOS(P<0.05),as well as decreased IL-1β,IL-6 and TNF-αand increased SOD and GSH-Px in right ventricular tissue(P<0.05),and the levels of PHB2 expression in the lung tissue were increased(P<0.05)and p-STAT3 expression was decreased(P<0.05)in HPH+PHB2 group.Conclusion:PHB2 alleviates right ventricular remodeling in HPH mice,which may be related to the inhibition of STAT3 phosphorylation by PHB2 in pulmonary artery smooth muscle.