Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury

Licia Totani, Antonio Piccoli, Giuseppe Dell'Elba, Amore Concetta, Angelomaria Di Santo, Nicola Martelli, Lorenzo Federico, Zehra Pamuklar, Susan S. Smyth, Virgilio Evangelista

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Objective - Platelet-neutrophil interactions play a key role in cardiovascular disease and inflammatory processes. Src family kinases mediate P-selectin glycoprotein ligand-1-Mac-1 cross talk necessary for firm platelet-neutrophil adhesion. Because Src family kinase activity can be regulated by cAMP-dependent pathways, in this work, we evaluated the role of phosphodiesterases in the signaling events that are required to sustain platelet-neutrophil interactions and neutrophil recruitment at the site of vascular injury. Approach And Results - In neutrophils exposed to P-selectin, selective phosphodiesterase 4 (PDE4) inhibition prevented Src family kinase-mediated phosphorylation of the proline-rich tyrosine kinase 2 on Tyr579/Tyr580. The effects of PDE4 inhibition required protein kinase A, likely through protein kinase A-mediated activation of COOH-terminal Src kinase, a major negative regulator of Src family kinases. PDE4, but not other phosphodiesterase inhibitors, reduced platelet-neutrophil conjugates as well as neutrophil firm adhesion on spread platelets under flow conditions. The effect of PDE4 inhibition on neutrophil adhesion was primarily mediated by downregulation of P-selectin-induced activation of Mac-1. In a murine model of endovascular injury, selective inhibition of PDE4 significantly reduced neutrophil recruitment at the site of vascular damage. Conclusions - This study identifies PDE4 as a central node in the signaling network that mediates platelet-neutrophil adhesion and suggests that pharmacological inhibition of PDE4 may represent a novel therapeutic avenue for the treatment of cardiovascular disease.

Original languageEnglish
Pages (from-to)1689-1696
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number8
StatePublished - Aug 2014


  • Neutrophils
  • Phosphodiesterase 4 inhibitors
  • Platelets

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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