Role of phosphodiesterase 2 in ischemia-induced endothelial barrier dysfunction and cardiac inflammation

In acute myocardial infarction (AMI), cytokines such as TNFα impair coronary endothelial barrier functions. This allows the transmigration of neutrophils, which attract monocytes and macrophages for the clearance of dead cells. Inflammation after ischemia is necessary, but too much inflammation is deleterious. In general, increased endothelial cAMP and/or cGMP levels are enhanced, whereas decreased cAMP/cGMP levels weaken the barrier. Such decreases can be evoked by phosphodiesterases (PDEs). Our project aims to characterize the role of the cyclic GMP-stimulated dual esterase PDE2 in the regulation of endothelial barrier functions and myocardial immune cell infiltration after ischemia.

In cultured human coronary microvascular endothelial cells (ECs), TNFα increased PDE2 expression together with augmented expression of proinflammatory adhesion proteins such as VCAM-1. Pharmacological inhibition of PDE2 enhanced endothelial cGMP/cAMP levels and attenuated thrombin-induced barrier dysfunction as well as TNFα-induced VCAM-1 expression. To dissect the pathophysiological relevance, we generated a novel genetic mouse model with conditional, endothelial-restricted PDE2 deletion. Immunoblotting and PDE2 activity assays demonstrated efficiency and selectivity. Such EC PDE2 KO mice exhibited no noticeable phenotypic changes. Under resting conditions, their arterial blood pressure and coronary EC barrier were unaltered. Experimental AMI was associated with significant increases in cardiac PDE2 expression. In control mice, this was concomitant to marked myocardial infiltration by neutrophils, monocytes/macrophages, and dendritic cells. Notably, in EC PDE2 KO mice, myocardial inflammation after ischemia was significantly reduced.

Understanding the role of PDE2 in the regulation of endothelial barrier functions may unravel targets for novel therapies of AMI.