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目的:探讨血管紧张素转换酶2(ACE2)基因敲除(KO)小鼠脑海马组织中脑源性神经营养因子(BDNF)信号的改变以及厄贝沙坦干预对该信号通路的影响。方法:采用10~11周龄ACE2KO(Ace2/y)小鼠每天分别给予血管紧张素II(Ang II)1型(AT1)受体阻断剂厄贝沙坦(50mg/kg)或安慰剂治疗,为期2周。正常野生型(WT;Ace2+/y)小鼠作为正常对照。用Western印迹检测小鼠海马组织中BDNF与细胞外信号调节激酶1/2(ERK1/2)水平。采用放射免疫法测定小鼠血浆血管紧张素水平。结果:与正常WT对照小鼠相比,ACE2KO小鼠海马组织中BDNF蛋白表达[(1±0.16)比(0.54±0.16)]及血浆Ang-(1-7)水平[(55.6±7.5)pg/ml比(42.8±5.8)pg/ml]明显下调,伴有ERK1/2磷酸化[(1±0.28)比(1.79±0.29)]明显增加(P均<0.01),而经厄贝沙坦治疗后,ACE2KO小鼠海马组织BDNF蛋白表达(0.88±0.13)及血浆Ang-(1-7)水平[(59.4±8.4)pg/ml]明显增加,伴有ERK1/2磷酸化水平(1.33±0.19)明显降低(P<0.05或<0.01)。结论:ACE2基因缺失小鼠存在海马组织中BDNF蛋白表达下调及ERK1/2磷酸化增强,而AT1受体阻断剂厄贝沙坦干预在改善ACE2基因缺失小鼠Ang-(1-7)水平与海马BDNF表达的同时,可降低海马ERK磷酸化信号,提示AT1受体阻断具有一定的脑保护效应。
Objective: To investigate the changes of brain-derived neurotrophic factor (BDNF) signal in brain tissue of angiotensin-converting enzyme 2 (ACE2) knockout (KO) mice and the effect of irbesartan on the signal pathway. METHODS: ACE2KO (Ace2 / y) mice, aged 10-11 weeks, were treated with irbesartan (50 mg / kg), an angiotensin II type 1 (AT1) receptor blocker, or placebo For 2 weeks. Normal wild-type (WT; Ace2 + / y) mice served as normal controls. Western blotting was used to detect the levels of BDNF and extracellular signal-regulated kinase 1/2 (ERK1 / 2) in the hippocampus of mice. The plasma level of angiotensin in mice was determined by radioimmunoassay. Results: Compared with normal WT control mice, the expression of BDNF protein in hippocampus of ACE2KO mice [(1 ± 0.16) vs (0.54 ± 0.16)] and plasma Ang- (1-7) levels [(55.6 ± 7.5) pg / ml ratio (42.8 ± 5.8) pg / ml] was significantly lower than that of the control group (P <0.01), accompanied by the phosphorylation of ERK1 / 2 (1.17 ± 0.29 vs 1.79 ± 0.29) After treatment, the expression of BDNF protein in hippocampus of ACE2KO mice (0.88 ± 0.13) and plasma Ang- (1-7) levels [(59.4 ± 8.4) pg / ml] were significantly increased with ERK1 / 2 phosphorylation 0.19) was significantly lower (P <0.05 or <0.01). CONCLUSION: The down-regulation of BDNF protein and the increase of ERK1 / 2 phosphorylation in hippocampus of ACE2-deficient mice are present in the ACE2-deficient mice, while the intervention of AT1 receptor antagonist Irbesartan improves the level of Ang- (1-7) in ACE2-deficient mice And BDNF expression in hippocampus at the same time, can reduce the phosphorylation of ERK signal in hippocampus, suggesting that AT1 receptor block has some brain protective effect.