Inhibition of Endothelial Phosphodiesterase 2A Attenuates Post-infarct Inflammation

After acute myocardial infarction (AMI), endothelial barrier dysfunction facilitates cardiac and sometimes remote pulmonary immune cell infiltration. Unraveling molecular pathways can provide targets for anti-inflammatory therapies. It is known that during bacterial pneumonia, tumor necrosis factor alpha (TNF-α)-driven endothelial up-regulation of the dual phosphodiesterase (PDE) 2A, reducing cyclic nucleotide levels, fosters lung hyperpermeability. We studied whether PDE2A also participates in endothelial hyperpermeability after AMI. In mice, 2 days after experimental AMI, cardiac and pulmonary endothelial cell (EC) PDE2A expression was increased. This was concomitant with the induction of proinflammatory adhesion proteins and immune cell extravasation. In cultured microvascular myocardial and pulmonary ECs, TNF-α and interleukin-1β, cytokines released during cardiac ischemia, increased PDE2A expression through p38 mitogen-activated protein kinase activation. Conversely, the PDE2A inhibitor BAY 60-7550 enhanced endothelial 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels and attenuated thrombin-induced leakiness as well as TNF-α- or interleukin-1β-stimulated vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression. To dissect the pathophysiological implications, we generated mice with EC-restricted PDE2A deletion (knockout). PDE2A ablation enhanced endothelial cGMP and cAMP levels and reduced cytokine-stimulated VCAM-1 expression. Accordingly, EC PDE2A knockout mice had diminished myocardial and pulmonary inflammation after AMI and reduced cardiac scarring and dysfunction. Our data indicate that endothelial induction of the cGMP and cAMP-degrading PDE2A participates in impaired cardiac and pulmonary microcirculatory barrier after AMI. Therefore, PDE2A might be a target for anti-inflammatory therapies.