缬沙坦和U0126对大鼠心房纤维化及连接蛋白40重塑的影响

[Effects of valsartan and U0126 on atrial fibrosis and connexin40 remodeling in rats].

作者信息

Zhang Wei-ze, Wang Zhi-gang, Chen Yong-qing, Ma Ling, Li Tao, Bao Hong-gang, Li Pei-hong

机构信息

The Cardiology Department of Lanzhou General Hospital of Lanzhou Military Area Command of Chinese PLA, Lanzhou 730050, China.

出版信息

Zhonghua Xin Xue Guan Bing Za Zhi. 2011 Dec;39(12):1129-34.

PMID:22336507

Abstract

OBJECTIVE

To explore the effects of valsartan and MEK1/2 inhibitor U0126 on atrial fibrosis and connexin40 (Cx40) remodeling in rats treated with isoproterenol (ISO).

METHODS

32 male SD rats were randomly divided into control group (A), ISO (5 mg · kg(-1) · d(-1) for 7 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 AngIIcontent 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 AngII 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 AngII 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.

摘要

目的

探讨缬沙坦和MEK1/2抑制剂U0126对异丙肾上腺素（ISO）处理的大鼠心房纤维化和连接蛋白40（Cx40）重塑的影响。

方法

32只雄性SD大鼠随机分为对照组（A组）、ISO（5mg·kg⁻¹·d⁻¹，连续7天）+二甲基亚砜（DMSO）组（B组）、ISO+U0126（0.5mg·kg⁻¹·d⁻¹，连续28天）组（C组，U0126溶于DMSO）、ISO+缬沙坦（30mg·kg⁻¹·d⁻¹，连续28天）+DMSO组（D组）。28天后处死大鼠。采用放射免疫法测定心肌组织中血管紧张素II（AngII）含量，免疫组化法检测磷酸化MEK1/2（P-MEK1/2）、磷酸化细胞外信号调节激酶1/2（P-ERK1/2）和Cx40，苏木精-伊红（HE）和Masson染色心脏切片观察心房纤维化情况。

结果

与A组相比，B、C、D组AngII含量显著升高[（368.243±6.283）ng/L、（357.175±5.944）ng/L、（359.908±2.496）ng/L对（250.380±4.261）ng/L，P<0.01]；与B组相比，C组和D组心房纤维化程度显著降低[心肌纤维化体积分数（CVF）：（10.260±0.525）%、（10.238±0.524）%对（78.710±1.587）%，P<0.01]，而A组无心房纤维化[CVF（9.025±0.456）%]；与A组相比，B组P-MEK1/2和P-ERK1/2表达显著上调（P-MEK1/2：0.311±0.007对0.203±0.009，P<0.01；P-ERK1/2：0.259±0.003对0.173±0.006，P<0.01），与B组相比，C组和D组显著降低（P-MEK1/2：0.212±0.004、0.213±0.005对0.311±0.007，P<0.01，P-ERK1/2：0.178±0.004、0.175±0.007对0.259±0.003，P<0.01）。与A组相比，B组Cx40含量明显降低且分布紊乱（0.199±0.007对0.241±0.004，P<0.01），C组和D组可部分逆转（0.239±0.037、0.235±0.006对0.199±0.007，P<0.01）。C组和D组所有参数相似（P>0.05）。