Abstract
ObjectiveTo analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO).Patients/MethodsPlatelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100).ResultsASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position −786 (T−786→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)1177, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser1177 phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser1177. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser1177. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets.ConclusionsFunctional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser1177.
Highlights
Nitric oxide (NO) is generated by conversion of L-arginine into L-citrulline and, in platelets, it seems to be predominantly produced by the activity of a constitutive NO synthase 3 (NOS3), small amounts of an inducible NOS (NOS2) isoform have been detected [1,2]
3.5 mg/ mL Collagen showed homozygosis for CC at 2786 in the 5-flaking region of NOS3 gene which it is in accordance with previous works demonstrating that T2786RC mutation in NOS3 gene promoter is associated with coronary ischemia and coronary spam [8,25]
It was observed that highest quartile of C-reactive protein elevation showed a significant benefit from aspirin treatment [27], it is not clear whether platelet resistance to analyse if platelet responsiveness to aspirin (ASA) may be associated with systemic inflammation
Summary
Nitric oxide (NO) is generated by conversion of L-arginine into L-citrulline and, in platelets, it seems to be predominantly produced by the activity of a constitutive NO synthase 3 (NOS3), small amounts of an inducible NOS (NOS2) isoform have been detected [1,2]. Platelet-derived NO acts as negative feedback mechanisms reducing the recruitment of new platelets to the growing thrombus [3,4]. Endogenous circulating L-arginine competitive antagonists, such as asymmetric dimethylarginine (ADMA), have been reported increased in pathophysiological conditions in which NO production was reduced [6]. In human platelets, ADMA may inhibit L-arginine transport [7]
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