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目的探讨ERK1/2通路抑制剂U0126对盐酸异丙基肾上腺素(ISO)诱导的大鼠心房纤维化和缝隙连接蛋白40(Cx40)重构的影响。方法将32只雄性SD大鼠随机等分为空白对照组、DMSO组、ISO[5 mg/(kg.d)]+DMSO组(模型组)和ISO[5 mg/(kg.d)]+U0126[0.5 mg/(kg.d)]+DMSO组(干预组)。每组1次/d给予相关试剂,连续7 d后处死大鼠并取心肌组织。用放射免疫法测血管紧张素Ⅱ(AngⅡ)含量;H-E和Masson染色法观察心肌纤维化程度;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 (1)空白对照组[(242.133±4.870)ng/L]与DMSO组[(239.412±1.795)ng/L]的AngⅡ含量差异无统计学意义,而模型组[(500.250±8.869)ng/L]和干预组[(498.695±9.340)ng/L]的AngⅡ含量较空白对照组与DMSO组均升高,差异有统计学意义(P均<0.01)。(2)空白对照组与DMSO组无心房纤维化,而干预组心房纤维化程度较模型组减弱(P<0.01)。(3)空白对照组与DMSO组中p-MEK1/2和p-ERK1/2的含量差异无统计学意义,模型组中两者含量较空白对照组与DMSO组均增加(P均<0.01),干预组中两者含量与空白对照组和DMSO组比较差异均无统计学意义,而与模型组比较差异有统计学意义(P<0.01)。(4)空白对照组与DMSO组中Cx40含量差异无统计学意义且呈线性分布于心肌细胞闰盘处,模型组中Cx40含量较空白对照组和DMSO组均减少(P均<0.01)且分布无规律性,而干预组中Cx40含量与空白对照组和DMSO组比较差异均无统计学意义且部分呈线性分布于心肌细胞闰盘处;干预组中Cx40含量减少程度较模型组减弱(P<0.01),且部分呈线性分布于心肌细胞闰盘处。结论心肌组织中AngⅡ含量长期升高可能参与了心房纤维化的形成和Cx40重构,U0126通过抑制ERK1/2通路激活可有效改善心房纤维化程度和Cx40重构。
Objective To investigate the effect of U0126, an ERK1 / 2 pathway inhibitor, on the remodeling of connexin 40 (Cx40) and atrial fibrillation induced by isoproterenol hydrochloride in rats. Methods Thirty-two male Sprague Dawley rats were randomly divided into control group, DMSO group, ISO [5 mg / (kg · d)] + DMSO group and ISO [5 mg / (kg · d) U0126 [0.5 mg / (kg.d)] + DMSO group (intervention group). Each group was given 1 / d related reagents, rats were sacrificed 7 days and myocardial tissue was taken. The content of angiotensin Ⅱ (AngⅡ) was measured by radioimmunoassay. The degree of myocardial fibrosis was observed by HE and Masson staining. The expression of p-MEK1 / 2, Phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1 / 2) and Cx40 expression. Results There was no significant difference in AngⅡconcentration between the blank control group [(242.133 ± 4.870) ng / L] and DMSO group [(239.412 ± 1.795) ng / L] L] and intervention group [(498.695 ± 9.340) ng / L] compared with the blank control group and DMSO group, the difference was statistically significant (P all <0.01). (2) There was no atrial fibrosis in blank control group and DMSO group, but the degree of atrial fibrosis in intervention group was weaker than that in model group (P <0.01). (3) The content of p-MEK1 / 2 and p-ERK1 / 2 in blank control group and DMSO group had no statistical significance. Compared with blank control group and DMSO group, There was no significant difference between the intervention group and the blank control group and the DMSO group, but the difference was statistically significant (P <0.01). (4) The content of Cx40 in blank control group and DMSO group had no statistical significance and was linear distribution in the intercalated cardiomyocytes. The content of Cx40 in model group was lower than that in blank control group and DMSO group (P <0.01) There was no significant difference between the intervention group and the blank control group and the DMSO group (P <0.05). The Cx40 content in the intervention group was not significantly different from that in the blank control group and the DMSO group (P < 0.01), and some of the linear distribution of myocardial cells in the intercalated disc. Conclusion The long-term increase of AngⅡ content in myocardium may be involved in the formation of atrial fibrosis and Cx40 remodeling. U0126 can effectively improve the degree of atrial fibrosis and Cx40 remodeling by inhibiting the activation of ERK1 / 2 pathway.