Rapid ischemic tolerance induced by adenosine preconditioning results in Bcl-2 interacting mediator of cell death (Bim) degradation by the proteasome

International Journal of Physiology, Pathophysiology and Pharmacology

Roger Pancoast Simon¹  Corrin Erin Clayton¹  Simon John Thompson¹  Robert Meller¹  Andrea Nicole Ordonez¹  Michelle Dawn Ashley¹  Veronica Joy Jessick¹ 

关键词: Adenosine;    rapid ischemic tolerance;    Bcl-2;    proteasome;    ubiquitin;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Rapid ischemic tolerance, induced one hour following ischemic preconditioning, is mediated via the ubiq-uitin-proteasome system and the degradation of the pro-apoptotic bcl-2 family protein Bim. Previous studies implicate adenosine A1 receptors in mediating rapid ischemic tolerance. Since the A1 adenosine receptor antagonist DPCPX (10µM) blocked rapid ischemic tolerance in our model, we investigated whether adenosine-mediated preconditioning induces rapid ischemic tolerance via the proteasomal degradation of Bim. Cultured rat cortical neurons were incubated for 60 minutes with either adenosine (1µM) or (-)-N⁶-(2-Phenyl-isopropyl) adenosine (RPIA (1µM)), prior to a harmful dose of ischemia (120min oxygen and glucose deprivation). Preconditioned cells had significantly lower levels of cell death following harmful ischemia when compared to non-preconditioned cells. The proteasome inhibitor MG132 (0.1µM) blocked the protective effect of adenosine pre-conditioning. Immunoblot analysis revealed a decrease in Bim protein levels in adenosine and RPIA preconditioned neurons. Adenosine preconditioning induced neuroprotection and Bim degradation was blocked by the MEK inhibitor UO126 (10µM). Our data suggests that pharmacological preconditioning with adenosine results in proteasomal Bim degradation mediated by p42/44 MAPK. Therefore, pharmacological approaches may be able to induce rapid ischemic tolerance via similar molecular mechanisms as ischemic preconditioning.

【 授权许可】

Unknown