Phosphodiesterase Type 4 Blockade Prevents Platelet-Mediated Neutrophil Recruitment at the Site of Vascular Injury

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 w...