OTUD4对慢性低压低氧所致右心室肥厚的调控作用及机制OA

OBJECTIVE To investigate the regulatory role and mechanism of OTU domain-containing deubiquitinase 4(OTUD4)in simulated hypobaric hypoxia-induced right ventricular hypertrophy(RVH).METHODS Wild-type(WT)and OTUD4 knockout(OTUD4-/-)mice were randomly divided by gender into eight groups:WT control groups,OTUD4-/-control groups,WT model groups,and OTUD4-/-model groups.The model groups were housed in a hypobaric hypoxia chamber simulating an altitude of 5 500 m for 28 consecutive days to establish a model of right ventricular hypertrophy.Cardiac ultrasound was performed to measure tricuspid annular plane systolic excursion(TAPSE),right ventricular free wall thickness(RVFWT),and peak pulmonary valve flow velocity(PPVFV).Masson staining was used to detect the size of fibrosis in myocardial tissues.The right ventricle,left ventricle,and interventricular septum were weighed to calculate the right ventricular hypertrophy index(RVHI).Serum levels of atrial natriuretic peptide(ANP)and tumor necrosis factor alpha(TNF-α)were measured using commercial kits.Western blotting was performed to detect the protein expression levels of OTUD4,hypoxia-induc-ible factor 1α(HIF-1α),phosphorylated AMP-activated protein kinase(p-AMPK),phosphorylated eukaryotic translation initiation factor 4E-binding protein 1(p-4EBP1),and phosphorylated mammalian target of rapamycin(p-mTOR).RESULTS Compared with the WT control group,OTUD4 expression levels in right ventricular myocardial tissues were significantly reduced in the OTUD4-/-control group,but no significant differences were observed in TAPSE,PPVFV,RVFWT,RVHI,sizes of right ventricular fibrosis,serum levels of ANP and TNF-α,or the expression levels of p-AMPK,p-4EBP1,HIF-1α,and p-mTOR in right ventricular myocardial tissues.Compared with the WT control group,TAPSE and PPVFV were significantly decreased,RVFWT,RVHI,sizes of right ventricular fibrosis,and serum ANP and TNF-α levels were significantly increased,p-AMPK expressions in right ventricular myocardial tis-sues were significantly decreased while those of OTUD4,p-4EBP1,p-mTOR,and HIF-1α were signifi-cantly increased in the WT model group.Compared with the WT model group,TAPSE and PPVFV were significantly increased,RVFWT,RVHI,sizes of right ventricular fibrosis,and serum ANP and TNF-α levels were significantly decreased,p-AMPK expressions in the right ventricle were significantly increased,while those of OTUD4,p-4EBP1,p-mTOR,and HIF-1α were significantly decreased in the OTUD4-/-model group.The results were consistent between the male and female mice.CONCLU-SION Inhibition of OTUD4 can reverse right ventricular hypertrophy and right ventricular dysfunction induced by hypobaric hypoxia exposure.This protective effect is accompanied by changes in the expressions of key molecules in the AMPK/mTOR/HIF-1α signaling pathway,suggesting that this path-way may be involved.