Title

 

Authors

E. Arnoletti

Doctorate School in Molecular and Cellular Physiology, Pharmacology and Toxicology
Division of Medical Pharmacology, Dept. of Anatomy, Pharmacology and Forensic Medicine, University of Torino, Torino, Italy

 

Abstract

Obestatin is a newly discovered amidated 23 aminoacid peptide encoded by the ghrelin gene, initially described as a physiological opponent to ghrelin in the regulation of food intake (1). A large body of evidence suggested that ghrelin and its derivatives have a wide array of actions including cardiovascular activities (2). Recently, we have identified specific obestatin receptors in rat heart, aortic tissue, primary cardiomyocytes, endothelial cells and related-cell lines (cardiomyoblasts H9c2 and bovine aortic endothelial cells, BAEC), suggesting that these tissues or cells are primary and direct targets of obestatin (3,4). Based on the foregoing, we have now investigated the effects of obestatin: a) in vitro, upon high-glucose (30 mM) induced oxidative stress on BAEC, b) ex vivo, upon ischemia and reperfusion (I/R) injury on isolated rat heart and isolated cardiomyocytes or H9c2 cell line, c) in vivo, on diabetic cardiometabolic alterations in an experimental rat model of type 1 diabetes induced by streptozotocin (STZ) treatment. We found that obestatin protects BAEC cells by the pro-oxidative damage induced by high-glucose concentrations and exerts anti-apoptotic effects. Furthermore, obestatin protects rat heart from I/R injury, reducing infarct size and lactate dehydrogenase (LDH) release, and improving cardio-hemodynamic performances, including the recovery of both diastolic and systolic ventricular pressure. In cardiomyoblast H9c2 cell line or in primary cardiomyocytes, obestatin exerts an anti-apoptotic effect reducing the activity of pro-apoptotic enzyme caspase-3 through activation of PI3K, ERK1/2 and PKCε signalling. Finally, obestatin displays significant beneficial effects against diabetic cardiometabolic alterations (5). In particular, in diabetic rats a subacute obestatin treatment (25 μg/Kg s.c. twice a day for 6 weeks) significantly reduced hypertriglyceridemia and hypercholesterolemia, but not hyperglycemia. Moreover, obestatin treatment significantly rescued both basal and cardiac contractility stimulated by the β-adrenoceptor agonist isoproterenol, together with β-adrenoceptors expression, all parameters strongly reduced in diabetic rats. In conclusion, these findings may have potentially important implications in preventing diabetic cardiovascular complications and in clinical conditions of cardio-degenerative disease and/or ischemic injury, where cell protection and improvement of ventricular function are highly desirable.

The author espresses sincere thanks to the tutor Prof. Giampiero Muccioli (University of Torino), and Professors Giuseppe Alloatti and Manuela Aragno (University of Torino) for scientific help.

1) Zhang JV et al. (2005) – Science 310:996-999
2) Zhang G et al. (2010) - Curr Cardiol Rev 6:62-70
3) Arnoletti E et al. (2008) - 10 th European Congress of Endocrinology, Berlin
4) Alloatti G et al. (2010) - Am J Physiol Heart Circ Physiol 299:H470-H481
5) Aragno M et al. (2011) - Diabetes, Paper submitted for publication