Neuronostatin inhibits cardiac contractile function via a protein kinase A- and JNK-dependent mechanism in murine hearts

Am J Physiol Regul Integr Comp Physiol. 2009 Sep;297(3):R682-9. doi: 10.1152/ajpregu.00196.2009. Epub 2009 Jun 24.


Neuronostatin, a newly identified peptide hormone sharing the same precursor with somatostatin, exerts multiple pharmacological effects in gastrointestinal tract, hypothalamus, and cerebellum. However, the cardiovascular effect of neuronostatin is unknown. The aim of this study was to elucidate the impact of neuronostatin on cardiac contractile function in murine hearts and isolated cardiomyocytes. Short-term exposure of neuronostatin depressed left ventricular developed pressure (LVDP), maximal velocity of pressure development (+/-dP/dt), and heart rate in Langendorff heart preparation. Consistently, neuronostatin inhibited peak shortening (PS) and maximal velocity of shortening/relengthening (+/-dL/dt) without affecting time-to-PS (TPS) and time-to-90% relengthening (TR(90)) in cardiomyocytes. The neuronostatin-elicited cardiomyocyte mechanical responses were mimicked by somatostatin, the other posttranslational product of preprosomatostatin. Furthermore, the neuronostatin-induced cardiomyocyte mechanical effects were ablated by the PKA inhibitor H89 (1 microM) and the Jun N-terminal kinase (JNK) inhibitor SP600125 (20 microM). The PKC inhibitor chelerythrine (1 microM) failed to alter neuronostatin-induced cardiomyocyte mechanical responses. To the contrary, chelerythrine, but not H89, abrogated somatostatin-induced cardiomyocyte contractile responses. Our results also showed enhanced c-fos and c-jun expression in response to neuronostatin exposure (0.5 to 2 h). Taken together, our data suggest that neuronostatin is a peptide hormone with overt cardiac depressant action. The neuronostatin-elicited cardiac contractile response appears to be mediated, at least in part, through a PKA- and/or JNK-dependent mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Female
  • Heart Rate
  • Immediate-Early Proteins / metabolism
  • In Vitro Techniques
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Mice
  • Myocardial Contraction* / drug effects
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Peptide Hormones / metabolism*
  • Perfusion
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Somatostatin / metabolism
  • Time Factors
  • Ventricular Function, Left
  • Ventricular Pressure


  • Immediate-Early Proteins
  • Peptide Hormones
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • neuronostatin, mouse
  • Somatostatin
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • JNK Mitogen-Activated Protein Kinases