Abstract WP117: Ischemic Post-conditioning Partially Reverses Cell Cycle Re-entry Following Transient Ischemia/Reperfusion Injury
Background and purpose—The neuroprotective effects of ischemic postconditioning (IPostC) are well established but the underlying mechanism is still unknown. We began to explore this critical gap in the field by genomic comparison of ischemic rat cortex following transient middle cerebral artery occlusion (tMCAO) alone or tMCAO+IPostC.
Methods and Results—Microarray analysis revealed that tMCAO-induced transcriptional changes in 40 cell cycle regulators were ameliorated by IPostC, suggesting that IPostC reversed neuronal cell cycle re-entry. RT-PCR, immunoblotting, and immunofluorescence were subsequently used to quantify or localize the cell proliferation marker proliferating cell nuclear antigen (PCNA), positive and negative cell cycle regulators, and related signaling molecules. As expected, IPostC reversed the rise in mRNA levels of positive cell cycle regulators cdcb1, cdk1, cdca2, cadca3, and cdca7. Elevations in cyclin D1 and neuronal cyclin A2 were similarly inhibited. tMCAO-induced phosphorylation of extracellular signal-regulated kinase (p-ERK), glycogen synthase kinase-3β (p-GS3K3β), and cAMP response element binding protein (p-CREB) were also all depressed by IPostC. Furthermore, p-ERK colocalized with neuronal cyclin A2.
Conclusions—The present study demonstrates the potent inhibitory effect of IPostC treatment on tMCAO-induced cell-cycle reentry and on ERK/CREB and GSK3β/CREB signaling. Because neuronal cell cycle re-entry is pro-apoptotic, these findings lend insight into potential mechanisms underlying neuroprotection with IPostC.
- © 2012 by American Heart Association, Inc.