Endothelial natriuretic peptide receptor-C: all clear?

Cardiovascular diseases remain the leading cause of death in industrialized countries. Central to this statistic is the lack of treatments to effectively prevent or reverse the severe pathologic remodeling that characterizes a failing heart. Ageing is a major risk factor for the development of heart hypertrophy and fibrosis. Natriuretic peptides, via their cGMP-synthesizing guanylyl cyclase receptors, GC-A (for ANP and BNP) and GC-B (for CNP), exert protective cardiovascular and metabolic actions. The role of their shared receptor-C (NPR-C), lacking the GC domain, is less clear. Depending on the cell type and biological context, NPR-C seems to either internalize the NPs or mediate their effects. Endothelial cells (ECs) express all three receptors for NPs. To dissect the impact of endothelial NPR-C on cardiovascular ageing, we generated mice with EC-restricted deletion (KO).

In control mice, ageing was associated with increased arterial blood pressure and progressive cardiac fibrosis and hypertrophy. EC NPR-C KO mice showed reduced clearance of ANP from the circulation and stabilized ANP and CNP plasma levels. Despite this, throughout various ages their blood pressure was not different from control littermates. Furthermore, cardiac interstitial collagen contents were unchanged. However, aging-related cardiac enlargement and cardiomyocyte hypertrophy were markedly blunted and left ventricular systolic and diastolic functions were preserved. This was linked to augmented cardiac cGMP levels and enhanced PKGI-dependent stimulation of antihypertrophic and lusitropic pathways in cardiomyocytes.

Chronic inhibition of the NPR-C-mediated endothelial clearance of NPs improves their protective cGMP-mediated cardiac effects, attenuating ageing-related heart hypertrophy and dysfunction despite elevated blood pressure.

Supported by the Deutsche Forschungsgemeinschaft (DFG KU 1037/14-1 and SFB 1525)