CONICET | Buscador de Institutos y Recursos Humanos

Background:The endothelial hormone C-typenatriuretic peptide (CNP) exerts paracrine vascular actions. These actions aremediated by a transmembrane guanylyl cyclase B (GC-B) receptor synthetizing cGMPas second messenger. In the heart this receptor is expressed in both cardiomyocytesand fibroblasts but the functional relevance is unclear. Here we studied the effectsof exogenous, synthetic CNP in two murine models of hypertensive heart diseases. Methods:To analyse the effects ofCNP on Angiotensin II (Ang II)-induced arterial hypertension and cardiac remodelling,mice were treated with vehicle (saline), CNP, Ang II or a combination of bothpeptides. Osmotic minipumps filled with Ang II (2000 ng/Kg BW/min) and/or CNP(50 ng/Kg/min) were implanted subcutaneously for 2 weeks. In a second series ofexperiments, mice were subjected to surgical transverse aortic constriction(TAC) for 2 weeks. During this time, CNP or vehicle were administered viaosmotic minipumps. Results: Infusion of Ang II increased systolic bloodpressure levels by 38 ± 3 mmHg (tail cuff measurements). TAC increased leftventricular (LV) afterload by 52 ± 4 mmHg (invasive hemodynamic measurements inanesthetized mice). Both procedures induced marked LV hypertrophy andinterstitial fibrosis and mild LV contractile dysfunction. This was accompaniedby increased LV mRNA expression of the hypertrophy marker brain natriureticpeptide (BNP) and the fibrosis marker collagen I. CNP did notattenuate the hypertensive actions of Ang II but significantly prevented thedevelopment of cardiac hypertrophy and fibrosis and the induction of BNP andcollagen I expression. In contrast in the TAC model CNP had no effect on thecellular and molecular LV remodelling. Notably, CNP did not alter baseline cardiac contraction and relaxationfunctions but significantly improved LV ejection fraction in the Ang II-treatedmice and, even more, fully prevented TAC-induced cardiac dysfunction. In isolated adultmurine cardiomyocytes CNP/GC-B/cGMP signaling activated the cGMP-dependentprotein kinase I (cGKI) to phosphorylate phospholamban (PLB) at Ser16. Conclusion:In our experimental studiesinfusion of a low dose CNP largely prevented the deleterious structural cardiacchanges which follow neurohormonal activation by Ang II. These anti-remodellingeffects of CNP possibly contribute to the improved cardiac contractilefunctions. Strikingly, these cardiac protective effects of CNP were fully bloodpressure independent. In the TAC model (with fixed afterload) CNP did notattenuate cardiac hypertrophy but still improved cardiac contractile function.The phosphorylation of PLB might participate in this effect. Our experimentalobservations suggest that the CNP?cyclic GMP pathwaymay represent a target for heart-protecting therapies. Acknowledgement:Supportedby the Comprehensive Heart Failure Center (BMBF 01 EO1004).