Nitric oxide-sensitive guanylyl cyclase is the only nitric oxide receptor mediating platelet inhibition

被引:94
|
作者
Dangel, O. [2 ]
Mergia, E. [2 ]
Karlisch, K. [2 ]
Groneberg, D. [1 ,2 ]
Koesling, D. [2 ]
Friebe, A. [1 ,2 ]
机构
[1] Univ Wurzburg, Inst Physiol 1, D-97070 Wurzburg, Germany
[2] Ruhr Univ Bochum, Fak Med, Inst Pharmakol & Toxikol, Bochum, Germany
关键词
guanylyl cyclase; hemostasis; knock-out mice; nitric oxide; platelets; CGMP-INDEPENDENT INHIBITION; CYCLIC-GMP; GUANOSINE; 3'; 5'-MONOPHOSPHATE; VASCULAR SYSTEM; S-NITROSYLATION; SMOOTH-MUSCLE; AGGREGATION; ADHESION; PHOSPHOPROTEIN; PROTEIN;
D O I
10.1111/j.1538-7836.2010.03806.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade is involved in the precise regulation of platelet responses. NO released from the endothelium is known to activate NO-sensitive guanylyl cyclase (NO-GC) in platelets. By the generation of cGMP and subsequent activation of cGMP-dependent protein kinase (PKG), NO-GC mediates the reduction of the intracellular calcium and inhibits platelet adhesion and aggregation. However, NO has been postulated to influence these platelet functions also via cGMP-independent mechanisms. Objective: We studied the effect of NO on platelets lacking NO-sensitive guanylyl cyclase with regards to aggregation, adhesion, calcium mobilization and bleeding time. Methods and results: Here, we show that NO signaling leading to inhibition of agonist-induced platelet aggregation is totally abrogated in platelets from mice deficient in NO-GC (GCKO). Even at millimolar concentrations none of the several different NO donors inhibited collagen-induced aggregation of GCKO platelets. In addition, NO neither affected adenosine 5'-diphosphate (ADP)-induced adhesion nor thrombin-induced calcium release in GCKO platelets. Although the NO-induced cGMP signal transduction was totally abrogated cyclic adenosine monophosphate (cAMP) signaling was still functional; however, cGMP/cAMP crosstalk was disturbed on the level of phosphodiesterase type 3 (PDE3). These in vitro data are completed by a reduced bleeding time indicating the lack of NO effect in vivo. Conclusions: We conclude that NO-GC is the only NO receptor in murine platelets mediating the inhibition of calcium release, adhesion and aggregation: lack of the enzyme leads to disturbance of primary hemostasis.
引用
收藏
页码:1343 / 1352
页数:10
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