A novel chimeric natriuretic peptide reduces cardiomyocyte hypertrophy through the NHE-1-calcineurin pathway.

aimsNatriuretic peptides (NPs) inhibit cardiomyocyte hypertrophy through a cyclic GMP (cGMP)-dependent process, although these effects are associated with substantial vasodilatation. In this study, we used CU-NP, a non-vasodilatating novel NP synthesized from the ring structure of human C-type NP (CNP) and both C- and N-termini of urodilatin, and investigated whether it can directly modulate cardiomyocyte hypertrophy. METHODS AND

resultsExperiments were carried out in cultured neonatal rat ventricular myocytes exposed to phenylephrine, angiotensin II, or endothelin-1 in the absence or presence of CU-NP. CU-NP produced a concentration- and time-dependent increase in intracellular cGMP levels. The hypertrophic responses to all agonists were abrogated by 10 nM CU-NP. CU-NP treatment also prevented increased activity, gene and protein expression of sodium-hydrogen exchanger-1 (NHE-1) as well as elevations in intracellular Na(+) concentrations caused by hypertrophic agents. In addition, these effects were associated with a more than two-fold increase in activity of the Ca(2+)-dependent protein phosphatase calcineurin that peaked 6 h after addition of hypertrophic stimuli. Early (1-3 h) calcineurin activation was unaffected by CU-NP, although activation at 6 and 24 h was prevented by CU-NP as was the resultant translocation of the transcriptional factor NFAT into nuclei.

conclusionOur study demonstrates a direct anti-hypertrophic effect of the chimeric peptide CU-NP via NHE-1 inhibition, thereby preventing calcineurin activation and NFAT nuclear import. Thus, CU-NP represents a novel fusion peptide of CNP and urodilatin that has the potential to be developed into a therapeutic agent to treat cardiac hypertrophy and heart failure.