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

Ana Kilić, Venkatesh Rajapurohitam, Sharon M. Sandberg, Asad Zeidan, J. Craig Hunter, Nazo Said Faruq, Candace Y. Lee, John C. Burnett, Morris Karmazyn

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25 Scopus citations

Abstract

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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)434-442
Number of pages9
JournalCardiovascular research
Volume88
Issue number3
DOIs
StatePublished - Dec 1 2010

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Keywords

  • Calcineurin
  • Cardiomyocytes
  • Hypertrophy
  • Natriuretic peptides
  • Sodium-hydrogen exchanger 1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kilić, A., Rajapurohitam, V., Sandberg, S. M., Zeidan, A., Hunter, J. C., Said Faruq, N., Lee, C. Y., Burnett, J. C., & Karmazyn, M. (2010). A novel chimeric natriuretic peptide reduces cardiomyocyte hypertrophy through the NHE-1-calcineurin pathway. Cardiovascular research, 88(3), 434-442. https://doi.org/10.1093/cvr/cvq254