Natriuretic peptides and nitric oxide induce endothelial apoptosis via a cGMP-dependent mechanism

被引:99
作者
Suenobu, N
Shichiri, M
Iwashina, M
Marumo, F
Hirata, Y
机构
[1] Tokyo Med & Dent Univ, Dept Internal Med 2, Div Endocrine Hypertens, Bunkyo Ku, Tokyo 113, Japan
[2] POLA Corp, Pola R&D Labs, Pharmaceut Res Labs, Yokohama, Kanagawa, Japan
关键词
natriuretic peptides; apoptosis; nitric oxide; endothelial cells;
D O I
10.1161/01.ATV.19.1.140
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Apoptosis is a mode of cell death in which the cell participates in its own demise. We studied whether endothelium-derived relaxing factor, nitric oxide (NO), and natriuretic peptides affect apoptosis of rat vascular endothelial cells via a cGMP-dependent pathway and whether such effects are antagonized by an endothelium-derived vasoconstrictor, endothelin-l (ET-1). Three natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide) induced endothelial apoptosis as demonstrated by nucleosomal laddering on agarose gel electrophoresis and by the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling method. This dose-dependent relation was assessed by quantifying the fragmented and intact DNA contents by the diphenylamine method. The atrial natriuretic peptide-induced endothelial apoptosis was completely blocked by a guanylate cyclase-coupled receptor antagonist (HS-142-1) and an inhibitor of cCMP-dependent protein kinase (KT5823). An NO donor, NOR3 {(+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3 -hexeneamide; FK409} also induced endothelial apoptosis; the effect of this compound was abrogated by KT5823 and an inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazoro[4,3-a]quinoxalin-1-one). A cGMP derivative, 8-bromo-cGMP, but not the cAMP derivative 8-bromo-cAMP, caused endothelial apoptosis; the effect of ODQ was also abrogated by KT5823. Endothelial apoptosis induced by ANP, NOR3, and 8-bromo-cGMP was similarly antagonized by ET-1. ANP, NOR3, and 8-bromo-cGMP caused marked accumulations of the tumor suppressor gene product p53 but not of bcl-2, as determined by Western blot analysis. These results demonstrate for the first time that endothelium-derived NO and natriuretic peptides are proapoptotic factors for endothelial cells, whereas the endothelium-derived vasoconstrictor ET-I is an antiapoptotic factor, suggesting that the countervailing balance between these vasodilators and vasoconstrictors, in addition to regulation of vascular tonus, may contribute to endothelial cell integrity.
引用
收藏
页码:140 / 146
页数:7
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