{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T14:08:13Z","timestamp":1777385293636,"version":"3.51.4"},"reference-count":72,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T00:00:00Z","timestamp":1628121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Heart Foundation","award":["2015T79"],"award-info":[{"award-number":["2015T79"]}]},{"name":"Netherlands Organization for Scientific Research","award":["Vidi 91716421"],"award-info":[{"award-number":["Vidi 91716421"]}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC Advanced \u2018VESCEL\u2019"],"award-info":[{"award-number":["ERC Advanced \u2018VESCEL\u2019"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["Horizon 2020 Marie Sklodowska-Curie \u2018EVOluTION\u2019 No. 675111"],"award-info":[{"award-number":["Horizon 2020 Marie Sklodowska-Curie \u2018EVOluTION\u2019 No. 675111"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2019 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\u22121. 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.<\/jats:p>","DOI":"10.3390\/cells10081998","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T21:43:53Z","timestamp":1628199833000},"page":"1998","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-9685","authenticated-orcid":false,"given":"Dani\u00eblle M.","family":"Coenen","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"},{"name":"Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra C. A.","family":"Heinzmann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Oggero","sequence":"additional","affiliation":[{"name":"Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3807-5035","authenticated-orcid":false,"given":"Hugo J.","family":"Albers","sequence":"additional","affiliation":[{"name":"BIOS Lab-on-a-Chip Group, Technical Medical Centre, MESA+ Institute for Nanotechnology, University of Twente, 7522 NB Enschede, The Netherlands"},{"name":"Applied Stem Cell Technologies Group, Technical Medical Centre, University of Twente, 7522 NB Enschede, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdolna","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Perrine","family":"Hagu\u00e9","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Faculty of Medicine, Universit\u00e9 Libre de Bruxelles, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-6532","authenticated-orcid":false,"given":"Marijke J. E.","family":"Kuijpers","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2193-5898","authenticated-orcid":false,"given":"Jean-Marie","family":"Vanderwinden","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Faculty of Medicine, Universit\u00e9 Libre de Bruxelles, B-1070 Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-4077","authenticated-orcid":false,"given":"Andries D.","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Applied Stem Cell Technologies Group, Technical Medical Centre, University of Twente, 7522 NB Enschede, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Perretti","sequence":"additional","affiliation":[{"name":"Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9955-9730","authenticated-orcid":false,"given":"Rory R.","family":"Koenen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7429-0109","authenticated-orcid":false,"given":"Judith M. 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