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 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.


RESULTS
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.


CONCLUSIONS
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.
Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, Turin, 10125, Italy. manuela.aragno@unito.it
Manuela
M
Aragno
Raffaella
R
Mastrocola
Corrado
C
Ghé
Elisa
E
Arnoletti
Eleonora
E
Bassino
Giuseppe
G
Alloatti
Giampiero
G
Muccioli
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006331:Heart Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D036361:Peptide Hormones / Q000494:pharmacology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D020127:Recovery of Function; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism
D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D036361:Peptide Hormones; D018342:Receptors, Adrenergic, beta-1; D014409:Tumor Necrosis Factor-alpha; C505798:obestatin, rat; D008687:Metformin; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains