Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II
Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II
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DOI：
10.1161/01.hyp.0000240064.19301.1b
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发表时间：
2006-10-01
期刊：
影响因子：
8.3
通讯作者：
Danser, A. H. Jan
中科院分区：
文献类型：
--
作者：
Saris, Jasper J.;'t Hoen, Peter A. C.;Danser, A. H. Jan
循环肾素原的组织积累导致血管紧张素生成，但也可能通过与最近克隆的肾素原受体结合，导致血管紧张素独立效应，如 p42/p44 丝裂原激活蛋白激酶 (MAPK) 激活和纤溶酶原激活剂抑制剂 (PAI)-1 释放。在这里，我们研究了肾素原是否在新生大鼠心肌细胞中发挥不依赖于血管紧张素的作用。多克隆抗体检测到这些细胞中的肾素（原）受体。肾素原既不影响 p42/p44 MAPK 也不影响 PAI-1。 PAI-1 释放确实发生在与血管紧张素原共孵育期间，表明这种效应是血管紧张素介导的。肾素原浓度依赖性激活 p38 MAPK，同时磷酸化 HSP27。后者的磷酸化被 p38 MAPK 抑制剂 SB203580 阻断。对肾素原刺激的大鼠肌细胞进行微阵列基因 (n=4800) 转录分析，检测到 260 个调节基因（与对照相比，P < 0.001），其中 p38 MAPK 和 HSP27 下游的基因参与肌动蛋白丝动力学，以及限制在血压和糖尿病 QTL 区域的（顺式）调节基因，如 Syntaxin-7。 代表性过高。 7 个选定基因（Opg、Timpl、Best5、Hsp27、pro-Anp、Col3a1 和 Hk2）的定量实时 RT-PCR 显示了时间调节，在肾素原暴露 4 小时后出现峰值水平。在肾素抑制剂阿利吉仑或血管紧张素 11 I 型受体拮抗剂依普罗沙坦存在的情况下，这种调节不会改变。最后，试点二维蛋白质组差异显示实验揭示了肾素原刺激 48 小时后心肌细胞中肌动蛋白细胞骨架的变化。总之，肾素原在心肌细胞中发挥不依赖于血管紧张素的作用。肾素原诱导的 p38 MAPK/HSP27 通路刺激，导致肌动蛋白丝动力学的改变，可能是先前在肝肾素原过度表达的大鼠中描述的严重心脏肥大的基础。
Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (P < 0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were over-represented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timpl, Best5, Hsp27, pro-Anp, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin 11 type I receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.