An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension
An angiotensin II- and NF-κB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension
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DOI：
10.1093/cvr/cvq031
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发表时间：
2010-07-01
影响因子：
10.8
通讯作者：
Haefliger, Jacques-Antoine
中科院分区：
文献类型：
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作者：
Alonso, Florian;Krattinger, Nathalie;Haefliger, Jacques-Antoine
连接蛋白（Cxs）在主动脉壁的收缩性中起作用。我们研究了内皮细胞的连接蛋白（EC; Cx 37，Cx40）和平滑肌细胞（SMC;我们将野生型（WT）小鼠和缺乏Cx40的小鼠作为实验对象，（Cx40（-/-））、两肾一夹手术或N-硝基-L-精氨酸甲酯治疗，其分别诱导肾素依赖性和非依赖性高血压。所有高血压小鼠的主动脉壁增厚，SMC中Cx 37和Cx45水平升高，EC中Cx40水平升高（Cx40（-/-）小鼠除外）。Cx43的上调，其S368磷酸化没有影响，只有在平滑肌细胞的肾素依赖性高血压模型。阻断Cx40（-/-）小鼠的肾素-血管紧张素系统使血压正常化，并防止主动脉增厚和Cx改变。WT动脉、颈动脉和肠系膜动脉离体暴露于生理相关水平的血管紧张素II（AngII）可增加Cx 43的水平，但不增加其他Cx的水平。在主动脉平滑肌细胞系A7 r5细胞中，AngII激活激酶依赖性通路，并诱导核因子-κ B（NF-κ B B）与Cx43基因启动子结合，增加Cx43表达。通过AngII激活细胞外信号调节激酶和NF-κ B通路，在肾素依赖性高血压中选择性增加Cx43。
Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension.We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappa B) to the Cx43 gene promoter, increasing Cx43 expression.In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappa B pathways.