C-type natriuretic peptide exerts blood pressure independent cardiac protective effects in hypertensive cardiac remodeling

PRENTKI SANTOS E; ABEßER M; SCHUH K; MICHEL K; VÖLKER K; KUHN M; WERNER F; BABA HA

Frankfurt

Conferencia; Joint International Meeting Perspectives in Vascular Biology; 2016

German Society for Microcirculation and Vascular Biology (GfMVB) and the Collaborative Research Centre 834 ?Endothelial Signalling and Vascular Repair? (SFB 834)

Question:C-type natriuretic peptide (CNP) is mainly produced by endothelial cells. Its actions are mediated by a guanylyl cyclase B (GC-B) receptor, which produces cGMP upon CNP binding. Even though the expression of GC-B has been demonstrated in both cardiac myocytes and fibroblasts, the functional relevance of CNP/GC-B/cGMP signalling in the heart remains unclear. In order to characterize CNP actions on the myocardium, the peptide was administrated in two experimental models of hypertensive heart diseases.Methods: Mice were treated with vehicle (saline), CNP, Angiotensin II (Ang II) or a combination of both. Osmotic minipumps filled with Ang II (2000 ng/kg/min) and/or CNP (50 ng/kg/min) were implanted subcutaneously for 2 weeks. In a second series of experiments, mice were subjected to surgical transverse aortic constriction (TAC) during 2 weeks and concomitantly treated with CNP or vehicle.Results: Both interventions resulted in significant left ventricular (LV) pressure overload. Ang II increased systolic blood pressure by 38 ± 3 mmHg (tail cuff in awake mice) while TAC enhanced LV afterload by 52 ± 4 mmHg (invasive hemodynamic measurements in anesthetized mice). Coherently, in both cases a marked LV hypertrophy and interstitial fibrosis were observed by means of morphometric analysis and increased levels of specific molecular markers, brain natriuretic peptide (BNP) for hypertrophy and collagen I for fibrosis. Though CNP did not attenuate hypertension produced by Ang II, it significantly prevented the hypertrophic and profibrotic actions of Ang II and TAC.To study cardiac contractile functions, LV pressure-volume loops were recorded (catheterization in anesthetized mice). LV contractile and relaxation functions of Ang II-treated mice were only mildly altered, while TAC markedly impaired LV function. CNP significantly improved LV contractility in Ang II-treated mice and fully prevented cardiac dysfunction induced by TAC.Conclusion: CNP largely attenuated the deleterious structural cardiac changes following Ang II neurohormonal activation or pressure overload induced by TAC. These anti-remodelling effects of CNP possibly contribute to the improvement of cardiac contractile functions. Strikingly, these effects were blood pressure independent. Our observations suggest that CNP signalling may represent a target for heart-protecting therapies.Acknowledgement: Supported by the DFG (SFB 688).