Endothelial Actions of ANP Enhance Myocardial Inflammatory Infiltration in the Early Phase After Acute Infarction
Rationale: In patients after acute myocardial infarction (AMI), the initial extent of necrosis and inflammation determine clinical outcome. One early event in AMI is the increased cardiac expression of atrial (ANP) and B-type natriuretic peptides (BNP), their plasma levels correlating with severity of ischemia. It was shown that NPs, via their cGMP-forming guanylyl cyclase-A (GC-A) receptor and cGMP-dependent kinase I (cGKI), strengthen systemic endothelial barrier properties in acute inflammation.
Objective: We studied whether endothelial actions of local NPs modulate myocardial injury and early inflammation after AMI.
Methods and Results: Necrosis and inflammation after experimental AMI were compared between control mice and littermates with endothelial-restricted inactivation of GC-A (EC GC-A KO) or cGKI (EC cGKI KO). Unexpectedly, myocardial infarct size and neutrophil infiltration/activity 2-days after AMI were attenuated in EC GC-A KO and unaltered in EC cGKI KO animals. Molecular studies revealed that hypoxia and TNF-α, conditions accompanying AMI, reduce the endothelial expression of cGKI and enhance cGMP-stimulated phosphodiesterase (PDE)2A levels. Real-time cAMP measurements in endothelial microdomains using a novel FRET biosensor revealed that PDE2 mediates ANP/cGMP-driven decreases of submembrane cAMP levels. Finally, intravital microscopy studies of the mouse cremaster microcirculation showed that TNF -induced endothelial NP/GC-A/cGMP/PDE2 signaling impairs endothelial barrier functions.
Conclusions: Hypoxia and cytokines such as TNF-α modify the endothelial postreceptor signaling pathways of NPs, with downregulation of cGKI, induction of PDE2A and altered cGMP/cAMP crosstalk. Increased expression of PDE2 can mediate hyperpermeability effects of paracrine endothelial NPs/GC-A/cGMP signaling and facilitate neutrophil extravasation during the early phase after MI.
- cyclic GMP
- guanylyl cyclase A
- phosphodiesterase 2A
- endothelial permeability
- acute myocardial infarction
- animal model cardiovascular disease
- atrial natriuretic peptide
- basic science
- endothelial cell
- Received July 12, 2015.
- Revision received May 2, 2016.
- Accepted May 3, 2016.