title: Contribution of the PI 3-kinase/Akt survival pathway toward osmotic preconditioning.
abstract: Osmolytes are rapidly lost from the ischemic heart, an effect thought to benefit the heart by reducing the osmotic load. However, the observation that chronic lowering of one of the prominent osmolytes, taurine, is more beneficial to the ischemic heart than acute taurine loss suggests that osmotic stress may benefit the ischemic heart through multiple mechanisms. The present study examines the possibility that chronic osmotic stress preconditions the heart in part by stimulating a cardioprotective, osmotic-linked signaling pathway. Hyperosmotic stress was produced by treating rat neonatal cardiomyocytes during the pre-hypoxic period with either the taurine depleting agent, beta-alanine (5 mM), or with medium containing 25 mM mannitol. The cells were then subjected to chemical hypoxia in medium containing 3 mM Amytal and 10 mM deoxyglucose but lacking beta-alanine and mannitol. Cells that had been pretreated with either 5 mM beta-alanine or 25 mM mannitol exhibited resistance against hypoxia-induced apoptosis and necrosis. Associated with the osmotically preconditioned state was the activation of Akt and the inactivation of the pro-apoptotic factor, Bad, both events blocked by the inhibition of PI 3-kinase. However, preconditioning the cardiomyocyte with mannitol had no effect on the generation of free radicals during the hypoxic period. Osmotic stress also promoted the upregulation of the anti-apoptotic factor, Bcl-2. Since inhibition of PI 3-kinase with Wortmannin also prevents osmotic-mediated cardioprotection, we conclude that hyperosmotic-mediated activation of the PI 3-kinase/Akt pathway contributes to osmotic preconditioning.
authors.affiliation: University of South Alabama, School of Medicine, Department of Pharmacology, Mobile, AL 36688, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Pastukh
authors.forename: Craig
authors.initials: C
authors.lastname: Ricci
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Solodushko
authors.forename: Mahmood
authors.initials: M
authors.lastname: Mozaffari
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Schaffer
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D004789:Enzyme Activation; D008353:Mannitol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009997:Osmotic Pressure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013481:Superoxides / Q000378:metabolism; D013654:Taurine / Q000037:antagonists & inhibitors; D000077191:Wortmannin; D051025:bcl-Associated Death Protein; D015091:beta-Alanine / Q000494:pharmacology
chemical_list: D000730:Androstadienes; D002352:Carrier Proteins; D008353:Mannitol; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D013481:Superoxides; D013654:Taurine; D000077191:Wortmannin; D051025:bcl-Associated Death Protein; D015091:beta-Alanine; C494821:Bad protein, rat; C494920:Akt1 protein, rat