Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II

被引:208
作者
Saris, Jasper J.
't Hoen, Peter A. C.
Garrelds, Ingrid M.
Dekkers, Dick H. W.
den Dunnen, Johan T.
Lamers, Jos M. J.
Danser, A. H. Jan
机构
[1] Erasmus MC, Dept Pharmacol, NL-3015 GE Rotterdam, Netherlands
[2] Erasmus MC, Dept Biochem, Rotterdam, Netherlands
[3] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands
[4] Leiden Univ, Med Ctr, Leiden Genome Technol Ctr, Leiden, Netherlands
关键词
p38 MAP kinase; actin; microarray; hypertrophy; HSP27;
D O I
10.1161/01.HYP.0000240064.19301.1b
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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.
引用
收藏
页码:564 / 571
页数:8
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