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European Journal of Heart Failure Advance Access originally published online on February 3, 2009
European Journal of Heart Failure 2009 11(4):336-341; doi:10.1093/eurjhf/hfp005
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Inhibition of platelet activation in rats with severe congestive heart failure by a novel endothelial nitric oxide synthase transcription enhancer

Andreas Schäfer1,*, Daniela Fraccarollo1, Julian Widder1, Martin Eigenthaler2, Georg Ertl1 and Johann Bauersachs1

1 Medizinische Klinik und Poliklinik I, Julius-Maximilians-Universität Würzburg, Josef Schneider Strasse 2, 97080 Würzburg, Germany
2 Institut für Klinische Biochemie und Pathobiochemie, Julius-Maximilians-Universität Würzburg, Würzburg, Germany

* Corresponding author. Tel: +49 931 201 1, Fax: +49 931 201 36131, Email: a.schaefer{at}medizin.uni-wuerzburg.de


  Abstract

Aims: Increased risk of thrombo-embolic events in congestive heart failure (CHF) has been attributed to a hypercoagulable state including vascular endothelial dysfunction and reduced bioavailability of nitric oxide (NO) as well as platelet activation. We investigated whether treatment with a novel endothelial NO synthase (eNOS)-transcription enhancer positively modulates systemic NO bioavailability and reduces platelet activation in rats with CHF.

Methods and results: After experimental myocardial infarction, male Wistar rats were treated with either placebo or the eNOS-transcription enhancer, AVE9488 (25 ppm/day) for 10 weeks. In rats with severe CHF (left ventricular end-diastolic pressure >15 mmHg), platelet vasodilator-stimulated phosphoprotein (VASP)-phosphorylation reflecting the integrity of the NO/cGMP pathway was significantly reduced (mean immunofluorescence at Ser157: Sham, 61.4 ± 9.1; CHF-Placebo, 37.4 ± 4.9; P < 0.05; Ser239: Sham, 18.1 ± 2.5; CHF-Placebo, 13.2 ± 0.6; P < 0.05). Platelet surface expression of P-selectin and glycoprotein 53 were increased in CHF rats compared with sham-operated animals. Chronic treatment with AVE9488 significantly enhanced platelet VASP-phosphorylation in CHF rats (Ser157: 70.4 ± 16.2; Ser239: 19.3 ± 1.8). In parallel, platelet surface expression of P-selectin and glycoprotein 53 was reduced in the treatment group.

Conclusion: Platelet activation was evident in CHF rats. Therapy with the eNOS-transcription enhancer, AVE9488, reduced platelet activation in parallel to normalization of platelet NO bioavailability.

Key Words: Heart failure • Platelets • Infarction • Nitric oxide • Endothelial function

Received July 21, 2008; Revised November 24, 2008; Accepted December 11, 2008


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