The online version of this article (doi:10.1186/1475-2840-11-129) contains supplementary material, which is available to authorized users.
Giuseppe Alloatti and Giampiero Muccioli contributed equally to this work.
No conflict of interest, financial or otherwise, are declared by the authors.
Authors’ contribution: experiments planning and manuscript drafting: MA, GA and GM; cell culture and animal treatment: CG, EA and RM; cardiac contractility studies: EB and GA; biochemical parameters detection, western blot and PCR: MA and RM. All author read and approved the final manuscript.
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.
Authors’ original file for figure 112933_2012_567_MOESM1_ESM.tiff
Authors’ original file for figure 212933_2012_567_MOESM2_ESM.tiff
Authors’ original file for figure 312933_2012_567_MOESM3_ESM.tiff
Authors’ original file for figure 412933_2012_567_MOESM4_ESM.tiff
Authors’ original file for figure 512933_2012_567_MOESM5_ESM.tiff
Authors’ original file for figure 612933_2012_567_MOESM6_ESM.tiff
Gourcerol H, Tache Y: Obestatin - a ghrelin associated peptide that does not hold its promise to suppress food intake and motility. Neurogastrenterol Motil. 2007, 19: 161-165. 10.1111/j.1365-2982.2007.00916.x. CrossRef
Granata R, Settanni F, Gallo D, Trovato L, Biancone L, Cantaluppi V, Nano R, Annunziata M, Campiglia P, Arnoletti E, Ghè C, Volante M, Papotti M, Muccioli G, Ghigo E: Obestatin promotes survival of pancreatic β-cells and human islets and induces expression of genes involved in the regulation of β-cell mass and function. Diabetes. 2008, 57: 967-79. 10.2337/db07-1104. CrossRefPubMed
Granata R, Volante M, Settanni F, Gauna C, Ghé C, Annunziata M, Deidda B, Gesmundo I, Abribat T, van der Lely AJ, Muccioli G, Ghigo E, Papotti M: Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats. J Mol Endocrinol. 2010, 45: 9-17. 10.1677/JME-09-0141. CrossRefPubMed
Granata R, Settanni F, Julien M, Nano R, Togliatto G, Trombetta A, Gallo D, Piemonti L, Brizzi MF, Abribat T, van Der Lely AJ, Ghigo E: Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats. J Med Chem. 2012, 55: 2585-96. 10.1021/jm201223m. CrossRefPubMed
Ozbay Y, Aydin S, Dagli AF, Akbulut M, Dagli N, Kilic N, Rahman A, Sahin I, Polat V, Ozercan HI, Arslan N, Sensoy D: Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease. BMB Rep. 2008, 41: 55-61. 10.5483/BMBRep.2008.41.1.055. CrossRefPubMed
Huda MS, Durham BH, Wong SP, Deepak D, Kerrigan D, McCulloch P, Ranganath L, Pinkney J, Wilding JP: Plasma obestatin levels are lower in obese and post-gastrectomy subjects, but do not change in response to a meal. Int J Obes (Lond). 2008, 32: 129-135. 10.1038/sj.ijo.0803694. CrossRef
Alloatti G, Arnoletti E, Bassino E, Penna C, Perrelli MG, Ghe C, Muccioli G: Obestatin affords cardioprotection to the ischemic-reperfused isolated rat heart and inhibits apoptosis in cultures of similarly stressed cardiomyocytes. Am J Physiol Heart Circ Physiol. 2010, 299: H470-481. 10.1152/ajpheart.00800.2009. CrossRefPubMed
Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A: Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/Akt. J Cell Biol. 2002, 159: 1029-1037. 10.1083/jcb.200207165. PubMedCentralCrossRefPubMed
Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG, Schlattner U, Neumann D, Brownlee M, Freeman MB, Goldman MH: Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004, 279 (42): 43940-51. 10.1074/jbc.M404421200. CrossRefPubMed
Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M: Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005, 280: 25196-25201. 10.1074/jbc.C500175200. CrossRefPubMed
Ravindranath V: Methods in Enzymology. Animal models and molecular markers for cerebral ischemia-reperfusion injury in brain. 1994, New York: Academic Press, 610-619. 233
Gando S, Hattori Y, Akaishi Y, Nishihira J, Kanno M: Impaired contractile response to β adrenoceptor stimulation in diabetic rat hearts: alterations in β adrenoceptors-G protein-adenylate cyclase system and phospholamban phosphorylation. J Pharmacol Exp Ther. 1997, 282: 475-84. PubMed
Granata R, Isgaard J, Alloatti G, Ghigo E: Cardiovascular actions of ghrelin and growth hormone-releasing hormone. Exp Biol Med. 2011, 236: 505-514. 10.1258/ebm.2011.010365. CrossRef
Nakamura K, Kusuoka H, Ambrosio G, Becker LC: Glycolysis is necessary to preserve myocardial Ca2+ homeostasis during beta-adrenergic stimulation. Am J Physiol. 1993, 264: H670-H678. PubMed
Pazos Y, Alvarez CJ, Camina JP, Casanueva FF: Stimulation of extracellular signal-regulated kinases and proliferation in the human gastric cancer cells KATO-III by obestatin. Growth Factors. 2008, 25: 373-381. CrossRef
Razny U, Kiec-Wilk B, Wator L, Polus A, Dyduch G, Solnica B, Malecki M, Tomaszewska R, Cooke JP, Dembinska-Kiec A: Increased nitric oxide availability attenuates high fat diet metabolic alterations and gene expression associated with insulin resistance. Cardiovasc Diabetol. 2011, 10: 68-10.1186/1475-2840-10-68. PubMedCentralCrossRefPubMed
- Obestatin induced recovery of myocardial dysfunction in type 1 diabetic rats: underlying mechanisms
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
e.Med Kampagnen-Visual, Mail Icon II