TY - JOUR
T1 - Contribution of the PI 3-kinase/Akt survival pathway toward osmotic preconditioning
AU - Pastukh, Viktor
AU - Ricci, Craig
AU - Solodushko, Viktoriya
AU - Mozaffari, Mahmood
AU - Schaffer, Stephen W.
N1 - Funding Information:
The present work was supported by a grant from the American Heart Association and the National Heart, Lung and Blood Institute Grant HL-63723.
PY - 2005/1
Y1 - 2005/1
N2 - 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, ß-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 ß-alanine and mannitol. Cells that had been pretreated with either 5 mM ß-alanine or 25 mM mannitol exhibited resistance gainst 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.
AB - 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, ß-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 ß-alanine and mannitol. Cells that had been pretreated with either 5 mM ß-alanine or 25 mM mannitol exhibited resistance gainst 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.
KW - Akt
KW - Apoptosis
KW - Bcl-2 family
KW - Hypoxia
KW - Osmotic stress
KW - Preconditioning
KW - Taurine
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U2 - 10.1007/s11010-005-2536-z
DO - 10.1007/s11010-005-2536-z
M3 - Article
C2 - 15786717
AN - SCOPUS:14244252655
SN - 0300-8177
VL - 269
SP - 59
EP - 67
JO - Molecular and Cellular Biochemistry
JF - Molecular and Cellular Biochemistry
IS - 1
ER -