Heart failure is associated with deficient endothelial
nitric oxide (NO) production as well as increased oxidative stress and accelerated NO degradation. The aim of this study was to evaluate platelet NO biosynthesis and
superoxide anion (O(2)(-)) production in patients with
heart failure.
METHODS AND RESULTS: In platelets from patients with
heart failure due to
idiopathic dilated cardiomyopathy (n= 16) and healthy control subjects (n= 23),
NO synthase (NOS) activity was evaluated by L-[(3)H]-
arginine to l-[(3)H]-
citrulline conversion, cGMP was determined by radioimmunoassay,
vasodilator-stimulated phosphoprotein (VASP: total and
serine-239-phosphorylated) was assessed by western blotting, and O(2)(-) production and O(2)(-) scavenging capacity were measured by
pholasin-enhanced chemiluminescence. In platelets from patients with
heart failure, basal NOS activity was higher than in those from controls; furthermore, whereas platelet NOS activity increased as expected in response to
albuterol or
collagen in controls, no increase occurred in platelets from
heart failure subjects. Despite this, basal intraplatelet NO-attributable cGMP was lower in
heart failure than in control subjects, as was serine-239 phosphorylation of VASP, suggesting a decrease in bioactive NO. Platelets from
heart failure subjects exhibited higher basal and
collagen-stimulated O(2)(-) production and impaired O(2)(-) scavenging capacity, resulting in higher oxidative stress, consistent with the observed decrease in bioactive NO.
CONCLUSION: In
heart failure, despite activation of NOS, platelets produce less bioactive NO, probably as a result of NO scavenging due to increased O(2)(-) production. This functional defect in the platelet
l-arginine/NO/
guanylyl cyclase pathway could contribute to the platelet activation observed in
heart failure.