Pathophysiological role and therapeutic targeting of endothelial C-type natriuretic peptide (CNP) and phosphodiesterase 2A in post-infarct inflammation

Project B2 studied how natriuretic peptide/cyclic GMP signalling and a negative cGMP-to-cAMP crosstalk in microcirculatory endothelial cells impact their barrier functions and thereby inflammation after acute myocardial infarction (AMI). 

Our data reveal that cytokines released in cardiac ischemia, such as TNFa and IL-1b, enhance the coronary as well as pulmonary endothelial expression and activity of the cGMP-stimulated dual cGMP/cAMP-degrading phosphodiesterase (PDE) 2A (1). Studies of cultured microvascular endothelial cells and of a genetic mouse model with conditional, endothelial PDE2A deletion demonstrate that PDE2A induction not only contributes to vascular barrier dysfunction and acute immune cell extravasation in the ischemic heart, but also to a disturbed proinflammatory interorgan communication between the heart and lung (1). Conversely, endothelial PDE2A deletion attenuated acute myocardial and pulmonary immune cell infiltration (2 days after experimental AMI) and subsequent adverse left ventricular scaring and dysfunction (2 weeks after AMI) (1). PDE2A might therefore be a target for anti-inflammatory strategies improving the coronary and pulmonary microcirculatory endothelial barrier. 

In addition, our project revealed that the endothelial hormone C-type natriuretic peptide (CNP) exerts autocrine and paracrine anti-inflammatory and antifibrotic effects in the heart and lung (2-5). Notably, these protective effects can be mimicked and reinforced by a single (monthly) subcutaneous injection of a recently developed long-acting CNP-analogue, MS~[Gln^6,14]CNP-38 (5), which also may have therapeutic relevance in inflammation-driven heart and lung fibrosis.