Endocrine Abstracts

Natriuretic peptides and their cGMP-synthesizing guanylyl cyclase receptors (GC-A, receptor for ANP and BNP; GC-B, for CNP) are critically involved in the regulation of arterial blood pressure (all NPs) and skeletal growth (only CNP). Both receptors are expressed in all cardiac cell types, although at different densities. GC-A is expressed at higher levels in endothelial and smooth muscle cells, whereas GC-B predominates in myocytes and fibroblasts. In heart failure (HF) patients, plasma levels of BNP and (less) ANP are elevated, correlating with the severity of the disease. However, despite these high NP levels, HF is in fact a state of combined deficiency of the active processed form of BNP and resistance to both NPs. Hence GC-A-mediated cGMP formation is markedly blunted, due to desensitization of the receptor. In contrast, GC-B activity is preserved. To study the specific cardiac impact of GC-A dysfunction, we generated various genetic mouse models with conditional, cell-restricted inactivation of this receptor. Our observations in these mouse models indicate that the NP/GC-A/cGMP system antagonizes the Ca²⁺_i-dependent hypertrophic growth response of myocytes to angiotensin II but not to β-adrenergic stimulation. The selectivity of this interaction is determined by activation of cGMP-dependent protein kinase I and phosphorylation of specific proteins regulating or mediating Ang II/AT₁-signalling (RGS2, TRPC3/6 channels). In addition our studies show that BNP, produced by myocytes in response to pressure-load or hypoxia, promotes the regeneration of neighboring endothelia via GC-A. This paracrine communication might be critically involved in coordinating myocyte hypertrophy and angiogenesis. We conclude that GC-A desensitization, leading to an endocrine but also local, cardiac imbalance between NPs and Ang II/aldosterone can contribute to the progression from hypertrophy to heart failure.

Supported by the Bundesministerium für Bildung und Forschung (BMBF01 EO1004).