cGMP‐independent inhibition of integrin α_IIbβ₃‐mediated platelet adhesion and outside‐in signalling by nitric oxide

Abstract

We examined the influence of S-nitrosoglutathione (GSNO) on a IIb b 3 integrin-mediated platelet adhesion to immobilised fibrinogen. GSNO induced a time-and concentrationdependent inhibition of platelet adhesion. Inhibition was cGMP-independent and associated with both reduced platelet spreading and protein tyrosine phosphorylation. To investigate the cGMP-independent effects of NO we evaluated integrin b 3 phosphorylation. Adhesion to fibrinogen induced rapid phosphorylation of b 3 on tyrosines 773 and 785, which was reduced by GSNO in a cGMP independent manner. Similar results were observed in suspended platelets indicating that NO-induced effects were independent of spreading-induced signalling. This is the first demonstration that NO directly regulates integrin b 3 phosphorylation.

Altered red cell and platelet adhesion in hemolytic diseases: Hereditary spherocytosis, paroxysmal nocturnal hemoglobinuria and sickle cell disease

“…NO signaling, in contrast, can alter cell adhesion mechanisms, inhibiting endothelial adhesion molecule expression and reducing the adhesive properties of leukocytes and platelets [14][15][16]. A possible interaction between hemolysis, decreased NO biovailability, and pathologic platelet activation has been suggested to contribute to thrombosis and pulmonary hypertension in SCD [17] and, potentially, other disorders of intravascular hemolysis.…”

Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells

“…In mice, the two tyrosine phosphorylation sites in the β3 subunit CT are Tyr747(Y747) and Tyr(Y759), which are involved in the signal transduction associated with tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin [14]. The corresponding tyrosine sites in humans are Y773 and Y785 [15]. Integrin tyrosine phosphorylation takes place upon ligand binding to the αIIbβ3 integrin.…”

S‐nitrosothiols as selective antithrombotic agents – possible mechanisms

“…A variety of molecular alterations have been proposed to mediate this process, including prevention of thromboxane synthesis (Tsikas et al, 1999), nitration of a-actinin (Marcondes et al, 2006), inhibition of the platelet P2Y 12 ADP receptor (or, more precisely its cellular signalling partners) (Kokkola et al, 2005) and either S-nitrosylation (Walsh et al, 2007) or altered phosphorylation (Oberprieler et al, 2007) of the important platelet integrin aIIbb3. There appears to be a requirement for extracellular generation of NO to occur before cyclic GMPindependent inhibition of calcium signalling and platelet aggregation can be brought about by NO donor compounds, including RSNOs (Crane et al, 2005).…”