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. 2014 Jun 27;3(3):e000920.
doi: 10.1161/JAHA.114.000920.

Different degrees of NADPH oxidase 2 regulation and in vivo platelet activation: lesson from chronic granulomatous disease

Roberto Carnevale  1 , Lorenzo Loffredo  1 , Valerio Sanguigni  2 , Alessandro Plebani  3 , Paolo Rossi  4 , Claudio Pignata  5 , Baldassarre Martire  6 , Andrea Finocchi  4 , Maria Cristina Pietrogrande  7 , Chiara Azzari  8 , Anna Rosa Soresina  3 , Silvana Martino  9 , Emilia Cirillo  5 , Francesco Martino  10 , Pasquale Pignatelli  1 , Francesco Violi  1
Affiliations

Different degrees of NADPH oxidase 2 regulation and in vivo platelet activation: lesson from chronic granulomatous disease

Roberto Carnevale et al. J Am Heart Assoc. .

Abstract

Background: In vitro study showed that NADPH oxidase (NOx), the most important enzyme producing reactive oxygen species (ROS), plays a role in the process of platelet activation. However, it is unclear if changes in its activity affect platelet activation in vivo.

Methods and results: In vivo and ex vivo experiments assessing platelet activation were investigated in healthy subjects, obese patients, and subjects with different low rates of NOx2 activity, namely X-linked chronic granulomatous disease (X-CGD) patients and X-CGD carriers. We included 27 X-CGD patients, 31 women carriers of hereditary deficiency of NOx2, 31 obese women, and 62 healthy subjects matched for sex and age. Plasma levels of soluble sCD40 L (sCD40L) and soluble P (sP)-selectin, 2 markers of in vivo platelet activation, were reduced in X-CGD patients (sCD40L=-55%; sP-selectin=-51%, P<0.001) and in X-CGD carriers (sCD40L=-41%; sP-selectin=-57%, P<0.001) compared with respective controls. Conversely, obese women, who disclosed NOx2 upregulation, had significantly higher plasma levels of sCD40L (+47%, P<0.001) and sP-selectin (+70%, P<0.001) compared with controls. Ex vivo study showed platelet isoprostane downexpression and enhanced platelet NO generation in both X-CGD patients and X-CGD carriers compared with controls; opposite findings were observed in obese patients. Correlation analysis showed that platelet NOx2 regulation was directly associated with plasma levels of sCD40L (R=0.336, P<0.001) and sP-selectin (R=0.441; P<0.001).

Conclusions: The study provides the first evidence that in vivo platelet activation is significantly and directly associated with NOx2 activity. Platelet NOx2 may be a novel target for platelet activation inhibition.

Keywords: NOx2; X‐CGD; oxidative stress; platelet activation.

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Figures

Figure 1.
Figure 1.
Plasma sCD40L (A), and plasma sP‐selectin (B) levels in adult controls, X‐CGD carriers, obese patients, X‐CGD patients and children controls (*P<0.001, **P<0.05). X‐CGD indicates X‐linked chronic granulomatous disease.
Figure 2.
Figure 2.
Platelet sNOx2‐dp release (A), platelet 8‐iso‐PGF2α formation (B) and platelet NOx production in X‐CGD patients and children controls (*P<0.001, **P<0.05). NOx indicates NADPH oxidase; X‐CGD, X‐linked chronic granulomatous disease.
Figure 3.
Figure 3.
Platelet sNOx2‐dp release (A), platelet 8‐iso‐PGF2α formation (B) and platelet NOx production in adult controls, X‐CGD carriers, and obese patients (*P<0.001, **P<0.05). NOx indicates NADPH oxidase; X‐CGD, X‐linked chronic granulomatous disease.
Figure 4.
Figure 4.
Platelet sCD40L (A), and platelet sP‐selectin (B) levels in adult controls, X‐CGD carriers, obese patients, X‐CGD patients and children controls (*P<0.001, **P<0.05). X‐CGD indicates X‐linked chronic granulomatous disease.
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