Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3-kinase/Akt-dependent pathway in rat aorta

被引:148
作者
Nishimatsu, H
Suzuki, E
Nagata, D
Moriyama, N
Satonaka, H
Walsh, K
Sata, M
Kangawa, K
Matsuo, H
Goto, A
Kitamura, T
Hirata, Y
机构
[1] Univ Tokyo, Fac Med, Dept Internal Med 2, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Fac Med, Dept Urol, Bunkyo Ku, Tokyo 1138655, Japan
[3] St Elizabeths Med Ctr Boston, Div Cardiovasc Res, Boston, MA USA
[4] Natl Cardiovasc Ctr, Res Inst, Fujishirodai, Japan
关键词
adrenomedullin; phosphatidylinositol; 3-kinase; Akt; nitric oxide; gene transfer;
D O I
10.1161/hh1301.092498
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
To study the mechanisms by which adrenomedullin (AM) induces endothelium-dependent vasorelaxation, we examined whether AM-induced endothelium-dependent vasodilation was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent pathway in rat aorta, because it was recently reported that PI3K/Akt was implicated in the activation of endothelial NO synthase, AM-induced vasorelaxation in thoracic aorta with intact endothelium was inhibited by pretreatment with PI3K inhibitors to the same level as that in endothelium-denuded aorta. AM elicited Akt phosphorylation in a time- and dose-dependent manner. AM-induced Akt phosphorylation was inhibited by pretreatment with a calmodulin-dependent protein kinase inhibitor as well as with PI3K inhibitors. When an adenovirus construct expressing a dominant-negative Akt mutant (Ad/dnAkt) was injected into abdominal aortas so that the mutant was expressed predominantly in the endothelium layer, AM-induced vasodilation was diminished to the same level as that in endothelium-denuded aortas. Finally, AM-induced cGMP production, which was used as an indicator for NO production, was suppressed by PI3K inhibition or by Ad/dnAkt infection into the endothelium. These results suggested that AM induced Act activation in the endothelium via the Ca2+/calmodulin-dependent pathway and that this was implicated in the production of NO, which in turn induced endothelium-dependent vasodilation in rat aorta.
引用
收藏
页码:63 / 70
页数:8
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