Obestatin induced recovery of myocardial dysfunction in type 1 diabetic rats: underlying mechanisms
- Equal contributors
1 Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, Turin, 10125, Italy
2 Department of Drug and Science Technology, University of Turin, Via Pietro Giuria 13, Turin, 10125, Italy
3 Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, Turin, 10123, Italy
Cardiovascular Diabetology 2012, 11:129 doi:10.1186/1475-2840-11-129Published: 15 October 2012
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.
Diabetes was induced by STZ injection (50 mg/kg) in Wistar rats (DM). OB was administered (25 μg/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 ß-adrenergic response were studied on isolated papillary muscles. Phosphorylation of AMPK, Akt, ERK1/2 and GSK3ß as well ß-1 adrenoreceptors levels were detected by western blot, while α-MHC was measured by RT-PCR.
OB preserved papillary muscle contractility (85 vs 27% of ND), ß-adrenergic response (103 vs 65% of ND), as well ß1-adrenoreceptors and α-MHC levels in diabetic myocardial tissue. Moreover, OB up-regulated the survival kinases Akt and ERK1/2, and enhanced AMPK and GSK3ß phosphorylation. OB corrected oxidative unbalance, reduced pro-inflammatory cytokine TNF-α plasma levels, NFkB translocation and pro-fibrogenic factors expression in diabetic myocardium.
OB displays a significant beneficial effect against the alterations of contractility and ß-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 ß1-adrenergic receptors and α-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 GSK3ß.