Dusp6 regulates mitochondrial fission to promote intermittent hypoxia-induced rat pulmonary arterial hypertension
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目的:探究双特异性磷酸酶6(Dusp6)对间歇性缺氧(IH)诱导的肺动脉高压(PAH)的影响及其机制.方法:利用基因表达数据库以及体内模型分析Dusp6的差异表达.随后将15只雄性SD大鼠随机分为正常组(Normal组)、慢性间歇缺氧组(CIH组,120 s循环,60 s 6％O2,60 s 21％O2,8 h/d,持续 6周)、CIH+Dusp6 抑制组(CIH+AAV1.Dusp6组),CIH处理6周后观察各组大鼠右心收缩压以及肺外周小动脉重塑程度.同时,将大鼠肺动脉平滑肌细胞(RPASMCs)分为正常组、间歇缺氧组(IH组,1h循环,30 min 1％O2,30 min 21％O2,持续24h)、间歇缺氧+Dusp6抑制组(IH+Si-Dusp6组),观察各组RPASMCs增殖、线粒体膜电位和线粒体分裂情况.结果:基因表达数据库以及体内模型显示,与正常组相比,IH组Dusp6表达升高.与正常组相比,CIH组大鼠右心收缩压升高,肺外周小动脉明显重塑;而与CIH组相比,CIH+AAV1.Dusp6组大鼠右心收缩压有所下降,肺外周小动脉重塑程度明显减轻.同时,IH能够诱导RPASMCs的增殖、线粒体膜电位降低和线粒体分裂,而抑制Dusp6能够明显减轻IH诱导的RPASMCs增殖、线粒体膜电位的降低和线粒体分裂.另外,Dusp6能够通过调节Drp1/ERK1/2通路而发挥作用.结论:抑制Dusp6表达可能通过Drp1/ERK1/2通路调节线粒体分裂从而抑制CIH诱导的大鼠肺动脉高压.
Objective:To investigate the impact of dual-specificity phosphatase 6(Dusp6)on intermittent hypoxia(IH)-induced pulmonary arterial hypertension(PAH)and elucidate the underlying mecha-nisms.Methods:Differential expression analysis of Dusp6 was performed using gene expression data-bases and in vivo models.Fifteen male SD rats were randomly assigned to the following groups:nor-mal group,chronic intermittent hypoxia(CIH)group(120 s cycling of 60 s 6％oxygen followed by 60 s normoxia,8 h/day,6 weeks),and CIH+Dusp6 inhibition group(CIH+AAV1.Dusp6 group).Af-ter 6 weeks of CIH exposure,right ventricular systolic pressure(RVSP)and pulmonary arteriole re-modeling were evaluated.Rat pulmonary artery smooth muscle cells(RPASMCs)were divided into the following groups:normal group,intermittent hypoxia(IH)group(1 h cycling of 30 min 1％O2 fol-lowed by 30 min 21％O2,24 h),and IH+Dusp6 inhibition group(IH+Si-Dusp6 group).RPASMCs proliferation,mitochondrial membrane potential,and mitochondrial fission were assessed in each group.Results:Gene expression databases and in vivo models demonstrated increased Dusp6 expres-sion in the IH group as compared with the normal group.In the CIH group,rats exhibited elevated RVSP and significant pulmonary arteriole remodeling as compared with the normal group.However,in the CIH+AAV1.Dusp6 group,RVSP was decreased,and pulmonary arteriole remodeling was significantly attenuated as compared with that respectively in the CIH group.IH induced RPASMCs proliferation,decreased mitochondrial membrane potential,and promoted mitochondrial fission,while Dusp6 inhibition significantly mitigated IH-induced RPASMCs proliferation,mitochondrial membrane potential reduction,and mitochondrial fission.Additionally,Dusp6 exerted its effects by modulating the Drp1/ERK1/2 pathway.Conclusion:Inhibition of Dusp6 expression may suppress CIH-induced pulmonary arterial hypertension by regulating mitochondrial fission through the Drp1/ERK1/2 pathway.
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