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

Abstract

Hua Y, Ma H, Samson WK, Ren J. Neuronostatin inhibits cardiac contractile function via a protein kinase A-and JNK-dependent mechanism in murine hearts. Am J Physiol Regul Integr Comp Physiol 297: R682-R689, 2009. First published June 24, 2009 doi:10.1152/ajpregu.00196.2009.-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 (ϮdP/dt), and heart rate in Langendorff heart preparation. Consistently, neuronostatin inhibited peak shortening (PS) and maximal velocity of shortening/relengthening (ϮdL/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 M) and the Jun N-terminal kinase (JNK) inhibitor SP600125 (20 M). The PKC inhibitor chelerythrine (1 M) 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.neuronostatin; cardiomyocytes; contraction; protein kinase; cell signaling SOMATOSTATIN [ALSO NAMED SOMATOTROPIN release-inhibiting factor or growth hormone inhibiting hormone], is a peptide hormone first found in the hypothalamus. It is also expressed in neuroendocrine organs, gastrointestinal tract, thyroid and adrenal glands, liver, spleen, kidney, prostate, inflammatory, and immune cells (23). Somatostatin has been shown to be involved in the regulatory processes of endocrine system, neurotransmission, cell proliferation, hormone secretion, and cardiovascular function (17). This peptide hormone contains two active isoforms (with 14 amino acids and 28 amino acids) produced by alternative cleavage of a single preproprotein. These two isoforms of somatostatin are capable of activating five related G protein-coupled membrane receptors with different affinity (9,31,32). To date, the majority of research on somatostatin has focused on hormonal regulation in gastrointestinal and nervous systems. More recent evidence has suggested the presence of the som...

Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107

“…Whether GPR107 is the initial receptor for neuronostatin in this model or is a receptor expressed in downstream neuronal circuits activated by neuronostatin cannot be determined by these studies; however, a combination of the in vitro and the in vivo results point promisingly to the identification of GPR107 as the cognate receptor for this recently discovered peptide hormone. This experimental approach can now be employed to study the potential physiological relevance of the additional actions of neuronostatin in brain (20), heart (10,19), and pancreas (15), studies that were not possible prior to identification of the potential neuronostatin receptor.…”

“…Neuronostatin activates KATOIII cells (15), cardiomyoctes (10,19), hypothalamic neurons (15), and pancreatic ␣-cells (15). Therefore, we screened these cell types for the candidate orphan GPCRs using PCR (Fig.…”

“…This elevation in MAP was found to be dependent upon two separate mechanisms: activation of the sympathetic nervous system and stimulation of vasopressin secretion from the posterior pituitary gland, since the first phase was blocked by pretreatment with phentolamine, while the second phase was reversed by pretreatment with a vasopressin receptor antagonist (20). In addition, neuronostatin directly altered the contractility of isolated cardiomyocytes and whole heart preparations via PKA and/or JNK-dependent mechanisms (10,19). Because neuronostatin is derived from the somatostatin preprohormone, any attempt to compromise the production of neuronostatin would result in loss of somatostatin as well.…”

“…NEURONOSTATIN, A PRODUCT OF the somatostatin preprohormone, is a recently described 13-amino acid peptide hormone that exerts multiple cardiovascular and metabolic actions in a variety of tissues (10,15,20). When injected into the lateral cerebroventricle (intracerebroventricularly) of adult, male rats, neuronostatin induced a significant, dose-related, and biphasic increase in mean arterial pressure (MAP) (15,20).…”

“…Neuronostatin directly initiates specific signaling cascades in at least four different cell types: hypothalamic neurons (15), cardiomyocytes (10,19), pancreatic ␣-cells (15), and a gastric tumor cell line, KATOIII (15). We reasoned that because these cell types responded to direct application of neuronostatin in vitro, they must express a neuronostatin receptor(s).…”