A novel catestatin-induced antiadrenergic mechanism triggered by the endothelial PI3KeNOS pathway in the myocardium

Abstract

Aims Catestatin (CST) is a chromogranin A (CgA)-derived peptide (hCgA352372) with three identified human variants (G364S/P370L/R374Q-CST) that show differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in the 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 resultsContractile force and Ca 2 transients were measured, respectively, on rat papillary muscles and isolated cardiomyocytes (CC) under basal conditions and after β-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (P Ser1179eNOS) were studied in bovine aortic endothelial (BAE-1) cells. Under basal conditions, wild-type CST (WT-CST, 1050 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 (550 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, Ca 2-independent increase in NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable with those of WT-CST, the G364S variant was ineffective on the same parameters. ConclusionOur results suggest that the anti-adrenergic action of CST depends on the endothelial PI3KAkteNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans. © 2011 The Author.