Stimulation of NPR-B by C-type natriuretic peptide enhanced beta1-adrenoceptor-evoked contractile responses and promoted cardiomyocyte apoptosis through cGMP-mediated inhibition of PDE3.
Does C-type natriuretic peptide enhance beta1-adrenoceptor signalling and promote apoptosis in failing hearts?
CNP enhances beta1-adrenergic signaling and promotes apoptosis in failing hearts via PDE3 inhibition, suggesting a potentially detrimental long-term effect similar to chronic beta-adrenergic stimulation.
AIMS: Whereas natriuretic peptides increase cGMP levels with beneficial cardiovascular effects through protein kinase G, we found an unexpected cardio-excitatory effect of C-type natriuretic peptide (CNP) through natriuretic peptide receptor B (NPR-B) stimulation in failing cardiac muscle and explored the mechanism. METHODS AND RESULTS: Heart failure was induced in male Wistar rats by coronary artery ligation. Contraction studies were performed in left ventricular muscle strips. Cyclic nucleotides were measured by radio- and enzyme immunoassay. Apoptosis was determined in isolated cardiomyocytes by Annexin-V/propidium iodide staining and phosphorylation of phospholamban (PLB) and troponin I was measured by western blotting. Stimulation of NPR-B enhanced beta1-adrenoceptor (beta1-AR)-evoked contractile responses through cGMP-mediated inhibition of phosphodiesterase 3 (PDE3). CNP enhanced beta1-AR-mediated increase of cAMP levels to the same extent as the selective PDE3 inhibitor cilostamide and increased beta1-AR-stimulated protein kinase A activity, as demonstrated by increased PLB and troponin I phosphorylation. CNP promoted cardiomyocyte apoptosis similar to inhibition of PDE3 by cilostamide, indicative of adverse effects of NPR-B signalling in failing hearts. CONCLUSION: An NPR-B-cGMP-PDE3 inhibitory pathway enhances beta(1)-AR-mediated responses and may in the long term be detrimental to the failing heart through mechanisms similar to those operating during treatment with PDE3 inhibitors or during chronic beta-adrenergic stimulation.
Qvigstad et al. (Mon,) conducted a other in Heart failure. C-type natriuretic peptide (CNP) was evaluated on beta1-adrenoceptor-evoked contractile responses and cardiomyocyte apoptosis. Stimulation of NPR-B by C-type natriuretic peptide enhanced beta1-adrenoceptor-evoked contractile responses and promoted cardiomyocyte apoptosis through cGMP-mediated inhibition of PDE3.