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Soluble guanylyl cyclase activation with HMR1766 attenuates platelet activation in diabetic rats
Andreas Schäfer1, Ulrike Flierl, Anna Kobsar
1Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
Insights
Chronic guanylyl cyclase activation in diabetic rats reduced platelet activation and markers of cardiovascular risk. This approach may help prevent adverse cardiovascular events in diabetes.
Area of Science:
- Cardiovascular Research
- Diabetology
- Pharmacology
Background:
- Platelet activation is a key factor in cardiovascular disease and mortality in diabetes.
- Impaired nitric oxide (NO)-mediated platelet inhibition is linked to increased platelet activation in experimental diabetes.
- Guanylyl cyclase activation can enhance the NO/cyclic guanosine monophosphate (cGMP) pathway.
Purpose of the Study:
- To investigate the effects of chronic guanylyl cyclase activation on platelet activation in a model of experimental diabetes mellitus.
- To determine if enhancing the NO/cGMP pathway could beneficially modulate platelet function in diabetic rats.
Main Methods:
- Diabetes was induced in male Wistar rats using streptozotocin.
- Rats received either placebo or the guanylyl cyclase activator HMR1766 (10 mg/kg twice daily) for two weeks.
- In vivo and in vitro assessments of platelet activation and reactivity were performed.
Main Results:
- Chronic HMR1766 treatment enhanced NO/cGMP-mediated signaling, evidenced by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets.
- Significant reductions were observed in platelet-fibrinogen binding, P-selectin surface expression, and platelet-derived microparticles.
- HMR1766 treatment also decreased the formation of platelet aggregates with other blood cells.
Conclusions:
- Chronic activation of soluble guanylyl cyclase in diabetic rats improved key markers of platelet activation.
- This therapeutic strategy offers a rationale approach for preventing cardiovascular complications associated with diabetes.
Objective:
Platelet activation significantly contributes to cardiovascular morbidity and mortality in diabetes. An association between impaired NO-mediated platelet inhibition and platelet activation has recently been demonstrated in experimental diabetes. Guanylyl cyclase activation enhances the reduced signaling via the NO/cGMP pathway. We investigated whether chronic guanylyl cyclase activation would beneficially modulate platelet activation in experimental diabetes mellitus.
Methods And Results:
Diabetes was induced by streptozotocin-injection in male Wistar rats. After 2 weeks, treatment with either placebo or the guanylyl cyclase activator HMR1766 (10 mg/kg twice daily by gavage) was initiated. Two weeks later, in vivo platelet activation and in vitro platelet reactivity were assessed. Chronic treatment with HMR1766 enhanced NO/cGMP-mediated signaling in platelets from diabetic rats determined by in vivo phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) at Ser157 and Ser239. In parallel, platelet-binding of fibrinogen, surface-expression of P-selectin, appearance of platelet-derived microparticles, and platelet-aggregates with other blood cells were significantly reduced by chronic treatment with HMR1766.
Conclusions:
Chronic activation of soluble guanylyl cyclase in diabetic rats improved markers of platelet activation and is a rationale approach for prevention of adverse cardiovascular events in diabetes.
