Aims: Catestatin (CST) is a Chromogranin A (CgA)-derived peptide (hCgA352-372) with three identified human variants (G364S/P370L/R374Q-CST), which showed differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in heart have remained elusive. Therefore, we sought to determine the mechanism of action of CST and its variants on ventricular myocardium and endothelial cells. Methods and Results: Contractile force and Ca2+ transients were measured respectively on rat papillary muscles and isolated cardiomyocytes (CC), in basal conditions and after β-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (PSer1179eNOS) were studied on Bovine Aortic Endothelial (BAE-1) cells. In basal conditions, wild-type-CST (WT-CST, 10-50 nM) transiently enhanced myocardial contractility. CST variants (G364S and P370L) exerted a comparable positive inotropic effect. The H1 histamine receptor antagonist Mepyramine abolished the increase of contractile force induced by WT-CST. Moreover WT-CST dose-dependently (5-50 nM) reduced the effect of β-adrenergic stimulation. This anti-adrenergic effect was not mediated by a direct action on CC, but involved a PI3K-dependent NO release from endocardial endothelial cells. Indeed, CST induced a Wortmannin-sensitive, Ca2+-independent increase of NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable to those of WT-CST, G364S-variant was ineffective on the same parameters. Conclusions: Our results suggest that the anti-adrenergic action of CST depends on the endothelial PI3K-Akt-eNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans.

A novel catestatin-induced antiadrenergic mechanism triggered by the endothelial PI3K–eNOS pathway in the myocardium

BASSINO, ELEONORA;FORNERO, SARA;GALLO, Maria Pia;RAMELLA, Roberta;LEVI, Renzo;ALLOATTI, Giuseppe
2011-01-01

Abstract

Aims: Catestatin (CST) is a Chromogranin A (CgA)-derived peptide (hCgA352-372) with three identified human variants (G364S/P370L/R374Q-CST), which showed differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in heart have remained elusive. Therefore, we sought to determine the mechanism of action of CST and its variants on ventricular myocardium and endothelial cells. Methods and Results: Contractile force and Ca2+ transients were measured respectively on rat papillary muscles and isolated cardiomyocytes (CC), in basal conditions and after β-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (PSer1179eNOS) were studied on Bovine Aortic Endothelial (BAE-1) cells. In basal conditions, wild-type-CST (WT-CST, 10-50 nM) transiently enhanced myocardial contractility. CST variants (G364S and P370L) exerted a comparable positive inotropic effect. The H1 histamine receptor antagonist Mepyramine abolished the increase of contractile force induced by WT-CST. Moreover WT-CST dose-dependently (5-50 nM) reduced the effect of β-adrenergic stimulation. This anti-adrenergic effect was not mediated by a direct action on CC, but involved a PI3K-dependent NO release from endocardial endothelial cells. Indeed, CST induced a Wortmannin-sensitive, Ca2+-independent increase of NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable to those of WT-CST, G364S-variant was ineffective on the same parameters. Conclusions: Our results suggest that the anti-adrenergic action of CST depends on the endothelial PI3K-Akt-eNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans.
2011
91
617
624
Cardiac contractility; Catestatin; Endothelial cells; Nitric oxide
E Bassino; S Fornero; MP Gallo; R Ramella; SK Mahata; B Tota; R Levi; G Alloatti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/85527
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