Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions

Abstract

Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets’ inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s−1. Similar results were obtained with blood from Pde3a deficient mice, indicating that cilostazol effects are mediated via PDE3A. Interestingly, cilostazol specifically reduced the release of phosphatidylserine-positive extracellular vesicles (EVs) from human platelets while not affecting total EV release. Both cilostazol and tadalafil reduced the interaction of human platelets with inflamed endothelium under arterial flow and the release of the chemokines CCL5 and CXCL4 from platelets. Moreover, cilostazol, but not tadalafil, reduced monocyte recruitment and platelet-monocyte interaction in vitro. Conclusions: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses.

Combined Antiplatelet Therapy Reduces the Proinflammatory Properties of Activated Platelets

“…In accordance with our recent observations, 29 inhibition of platelet cAMP via PDE3 with cilostazol was shown to have an inhibiting effect on chemokine CCL5 release upon stimulation with both convulxin and thrombin ( Figs. 5A , B and 6A , B ), while CXCL4 release was significantly inhibited by cilostazol only after stimulation with thrombin ( Figs.…”

“…In accordance with our recent observations [29], inhibition of platelet cAMP via PDE3 with cilostazol was shown to have an inhibiting effect on chemokine CCL5 release upon stimulation with both convulxin or thrombin (Figure 5A,B and 6A,B), while CXCL4 release was significantly inhibited by cilostazol only after stimulation with thrombin (Figure 5C,D and 6C,D). To investigate whether cilostazol has an additional effect on CCL5 and CXCL4 release from ASA-treated platelets, these platelets were incubated with cilostazol for 10 min prior to platelet activation.…”

“…So far, this study has focussed on the effect of antiplatelet medications and combinations on the inflammatory properties of platelets. Interestingly, we have observed differential protein and extracellular vesicle secretion patterns after platelet activation throughout this, and in other studies [19,29,53,54]. In this study, we have observed differential CCL5 and CXCL4 release under the influence of different antiplatelet medications.…”

“…ment [29]. In this study, the combination of ASA and cilostazol did not further inhibit chemokine release after platelet activation compared to ASA alone.…”

“…Interestingly, we have observed differential protein and extracellular vesicle secretion patterns after platelet activation throughout this, and in other studies. 19 29 53 54 In this study, we have observed differential CCL5 and CXCL4 release under the influence of different antiplatelet medications. This would suggest that these chemokines are differently packaged inside the α-granule of platelets and that their differential release is governed by autocrine feedback activation mechanisms.…”