Obestatin induced recovery of myocardial dysfunction in type 1 diabetic rats: underlying mechanisms

Background: The aim of this study was to investigate whether obestatin (OB), a peptide mediator encoded by the ghrelin gene exerting a protective effect in ischemic reperfused heart, is able to reduce cardiac dysfunctions in adult diabetic rats. Methods: Diabetes was induced by STZ injection (50 mg/kg) in Wistar rats (DM). OB was administered (25 mu g/kg) twice a day for 6 weeks. Non-diabetic (ND) rats and DM rats were distributed into four groups: untreated ND, OB-treated ND, untreated DM, OB-treated DM. Cardiac contractility and beta-adrenergic response were studied on isolated papillary muscles. Phosphorylation of AMPK, Akt, ERK1/2 and GSK3 beta as well beta-1 adrenoreceptors levels were detected by western blot, while alpha-MHC was measured by RT-PCR. Results: OB preserved papillary muscle contractility (85 vs 27% of ND), beta-adrenergic response (103 vs 65% of ND), as well beta 1-adrenoreceptors and alpha-MHC levels in diabetic myocardial tissue. Moreover, OB up-regulated the survival kinases Akt and ERK1/2, and enhanced AMPK and GSK3 beta phosphorylation. OB corrected oxidative unbalance, reduced pro-inflammatory cytokine TNF-alpha plasma levels, NFkB translocation and pro-fibrogenic factors expression in diabetic myocardium. Conclusions: OB displays a significant beneficial effect against the alterations of contractility and beta-adrenergic response in the heart of STZ-treated diabetic rats, which was mainly associated with the ability of OB to up-regulate the transcription of beta 1-adrenergic receptors and alpha-MHC; this protective effect was accompanied by the ability to restore oxidative balance and to promote phosphorylation/modulation of AMPK and pro-survival kinases such as Akt, ERK1/2 and GSK3 beta.