Cardiac atrial natriuretic peptide (ANP) has an important physiological role in the maintenance of arterial blood pressure and volume. Its cGMP-forming guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance is controversial. Local and plasma levels of ANP are markedly elevated after acute myocardial infarction (AMI), but the myocardial effect is largely unknown. To elucidate whether in this situation NPs modulate the barrier properties of the coronary endothelium, here we compared myocardial infarct size and inflammation in mice with endothelial-restricted deletion of the GC-A receptor (EC GC-A KO) and control littermates subjected to 48h of coronary artery occlusion without reperfusion.

Consistent with our previous observations (Sabrane et al.J Clin Invest2005), EC GC-A KO mice exhibited mild but significant arterial hypertension (tail cuff measurements), hypervolemia (evans blue dilution method) and cardiac hypertrophy. Intriguingly, despite these alterations, infarct sizes following coronary occlusion were significantly smaller (by ~ 18%, as determined by triphenyltetrazolium chloride staining of cardiac sections), and neutrophil infiltration was diminished (by ~ 14%; immunohistochemistry). In an additional experimental series, inflammatory cell infiltration was quantified by FACS analysis of enzymatically digested hearts. The results demonstrated a selective decrease of neutrophiles in EC GC-A KO hearts after coronary occlusion, whereas cardiac infiltration by macrophages, monocytes and T-lymphocytes was not different between genotypes.

We conclude that ANP, via endothelial GC-A/cGMP signaling, acts as local proinflammatory mediator which activates the coronary endothelium to recruit neutrophiles in the setting of AMI.

(Supported by IZKF Würzburg and SFB 688).