摘要目的 探讨缬沙坦与U0126对血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)诱导的大鼠心房纤维化和缝隙连接蛋白40( connexin 40,Cx40)重构的影响.方法 将32只雄性SD大鼠随机分为空白对照组(A组)、盐酸异丙基肾上腺素( isopreterenol,ISO)+二甲基亚砜(DMSO)组(B组)、ISO+U0126组(C组,U0126溶于DMSO中)、ISO+缬沙坦+DMSO组(D组).给药28 d后处死大鼠取心肌组织,放射免疫法测Ang Ⅱ含量;HE和Masson染色法观察纤维化程度即胶原容积分数(CVF);免疫组化法测定磷酸化丝裂原活化蛋白激酶激酶1/2(P-MEK1/2)、磷酸化细胞外信号调节激酶1/2( P-ERK1/2)以及Cx40的表达.结果 B、C、D组中Ang Ⅱ含量较A组明显升高[分别为(368.243±6.283)ng/L、(357.175±5.944) ng/L、(359.908±2.496) ng/L比(250.380±4.261) ng/L,P＜0.01];A组CVF(9.025 ±0.456)％,显示无心房纤维化;C组和D组较B组心房纤维化程度明显减弱[CVF分别为(10.260±0.525)％、(10.238 ±0.524)％比(78.710±1.587)％,P＜0.01],C组和D组之间差异无统计学意义(P＞0.05);B组较A组中P-MEK1/2(0.311±0.007比0.203±0.009,P＜0.01)和P-ERK1/2含量明显增加(0.259±0.003比0.173±0.006,P＜0.01),而C组和D组中含量较B组明显减少(P-MEK1/2分别为0.212±0.004、0.213±0.005比0.311±0.007,P＜0.01;P-ERK1/2分别为0.178±0.004、0.175 ±0.007比0.259±0.003,P＜0.01),C组和D组之间差异无统计学意义(P＞0.05);B组较A组Cx40含量明显减少(0.199±0.007比0.241±0.004,P＜0.01)且分布紊乱,C组和D组中含量较B组减少程度明显减轻(分别为0.239±0.037、0.235±0.006比0.199±0.007,P＜0.01)且部分呈线性分布于闰盘,C组和D组之间差异无统计学意义(P＞0.05).结论 心肌组织中Ang Ⅱ含量长期升高可能参与心房纤维化的形成和Cx40重构,缬沙坦与U0126通过抑制ERK通路的不同位点,在改善心房纤维化程度和Cx40重构方面发挥相似的作用.

abstractsObjective To explore the effects of valsartan and MEK1/2 inhibitor U0126 on atrial fibrosis and connexin40 (Cx40) remodeling in rats treated with isopreterenol (ISO).Methods 32 male SD rats were randomly divided into control group (A),ISO (5 mg · kg-1 · d-1 for7 days) + DMSO group (B),ISO + U0126 (0.5 mg · kg-1 · d-1 for 28 days) group (C,U0126 was dissolved in DMSO),ISO +valsartan (30 mg · kg-1 · d-1 for 28 days) + DMSO group (D).Rats were sacrificed after 28 days.The AngⅡ content in myocardial tissue was measured by radioimmunoassay,P-MEK1/2,P-ERK1/2 and Cx40 was detected by immunohistochemistry,atrial fibrosis was determined on HE and Masson stained heart sections.Results The content of Ang Ⅱ was significantly higher in group B,C and D compared with group A [ (368.243 ±6.283 ) ng/L,( 357.175 ± 5.944 ) ng/L,( 359.908 ± 2.496 ) ng/L vs ( 250.380 ± 4.261 )ng/L,P ＜0.01 ] ; the degree of atrial fibrosis was significantly lower in group C and D compared with group B [CVF(10.260 ±0.525)％,(10.238 ±0.524)％ vs (78.710 ± 1.587)％,P＜0.01 ] while there was no atrial fibrosis in group A [ CVF(9.025 ± 0.456)％ ] ; the expression of P-MEK1/2 and P-ERK1/2 was significantly upregulated in group B compared with group A ( P-MEK1/2:0.311 ± 0.007 vs 0.203 ± 0.009,P ＜0.01 ; P-ERK1/2:0.259 ±0.003 vs 0.173 ±0.006,P ＜0.01 ) and significantly lower in group C and D compared with group B (P-MEK1/2:0.212 ± 0.004,0.213 ± 0.005 vs 0.311 ± 0.007,P ＜0.01,P-ERK1/2:0.178 ±0.004,0.175 ±0.007 vs 0.259 ±0.003,P ＜0.01 ).The content of Cx40 was obviously reduced and the distribution of Cx40 was disordered in group B compared with A (0.199 ±0.007 vs 0.241 ±0.004,P＜0.01) which could be partly reversed in group C and D ( 0.239 ±0.037,0.235 ±0.006 vs 0.199 ± 0.007,P ＜ 0.01 ).All parameters in group C and D were similar ( P ＞ 0.05 ).Conclusion The chronically elevated Ang Ⅱ content in myocardium may be related to atrial fibrosis and Cx40 remodeling in this model,valsartan and U0126 were equivalent on attenuating atrial fibrosis and Cx40 remodeling by inhibiting ERK pathways at different levels.