Intracellular Angiotensin II and cell growth of vascular smooth muscle cells

被引:32
作者
Filipeanu, CM [1 ]
Henning, RH [1 ]
de Zeeuw, D [1 ]
Nelemans, A [1 ]
机构
[1] Univ Groningen, Dept Clin Pharmacol, NL-9713 AV Groningen, Netherlands
关键词
intracellular angiotensin II; growth; losartan; PD123319; CGP42112A; PI-3; kinase; MAP kinase; A7r5; cells;
D O I
10.1038/sj.bjp.0703984
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 We recently demonstrated that intracellular application of Angiotensin II (Angiotensin IIintr) induces rat aorta contraction independent of plasma membrane Angiotensin II receptors. In this study we investigated the effects of Angiotensin IIintr on cell growth in A7r5 smooth muscle cells. 2 DNA-synthesis was increased dose-dependently by liposomes filled with Angiotensin II as measured by [H-3]-thymidine incorporation at high (EC50 = 27 +/- 6 pM) and low (EC50 = 14 +/- 5 nM) affinity binding sites with increases in E-max of 58 +/- 4 and 37 +/- 4% above quiescent cells, respectively. Cell growth was corroborated by an increase in cell number. 3 Extracellular Angiotensin II (10 pM-10 muM) did not modify [H-3]-thymidine incorporation. 4 Growth effects of Angiotensin IIintr mediated via high affinity sites were inhibited by liposomes filled with 1 muM Of the non-peptidergic antagonists losartan (AT(1)-receptor) or PD123319 (AT(2)-receptor) or with the peptidergic agonist (GP42112A AT(2)-receptor). E-max values were decreased to 30 +/- 3, 29 +/- 4 and 4 +/- 2%, respectively, without changes in EC50 The Angiotensin IIintr effect via low affinity sites was only antagonized by CGP42112A (E-max = 11 +/- 3%), while losartan and PD123319 increased E-max to 69 +/- 4%. Intracellular applications were ineffective in the absence of Angiotensin IIintr 5 Neither intracellular nor extracellular Angiotensin I (1 muM) were effective. 6 The Angiotensin IIintr induced growth response was blocked by selective inhibition of phosphatidyl inositol 3-kinase (PI-3K) by wortmannin (1 muM) and of the mitogen-activated protein kinase (MAPK/ERK) pathway by PD98059 (1 muM) to 61 +/- 14 and 4 +/- 8% of control, respectively. 7 These data demonstrate that Angiotensin IIintr induces cell growth through atypical AT-receptors via a PI-3K and MAPK/ERK-sensitive pathway.
引用
收藏
页码:1590 / 1596
页数:7
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