Ischemic Preconditioning Reduces Neurovascular Damage After Hypoxia-Ischemia Via the Cellular Inhibitor of Apoptosis 1 in Neonatal Brain
Background and Purpose—The neurovascular unit is a major target of hypoxia-ischemia (HI) injury in the neonatal brain. Although neurons are the cellular target of ischemic preconditioning (IP), vessel tolerance also contributes greatly to protection. Nerves and vessels cross-talk and use common signals during development. Cellular inhibitor of apoptosis 1 (cIAP1) is an important regulator that inhibits apoptosis. This study hypothesized that cIAP1 is a shared molecule underlying IP-mediated neurovascular protection against HI in the neonatal brain.
Methods—In vivo IP was induced by 2-hour reversible occlusion of right carotid artery 24 hours before HI on postpartum day 7 in rat pups. In vitro oxygen–glucose deprivation (OGD) preconditioning was established in SH-SY5Y neuronal cells and in human microvascular endothelial cell-1 vascular endothelial cells. cIAP1 expression was inhibited by cIAP1 small interfering RNA in vivo or by lentivirus-mediated short hairpin RNA in vitro, or was upregulated by the lentiviral expression system.
Results—IP reduced apoptosis, selectively increased cIAP1 in neurons and vascular endothelial cells, and provided long-term neuroprotection against HI. Intracerebroventricular delivery of cIAP1 small interfering RNA significantly attenuated IP-mediated cIAP1 upregulation and neuroprotection in vivo. In vitro, OGD preconditioning induced cIAP1 and protected against OGD cell death in SH-SY5Y neuronal and human microvascular endothelial cells-1. Knockdown of cIAP1 by lentivirus-mediated short hairpin RNA decreased the protective effect of OGD preconditioning in SH-SY5Y and human microvascular endothelial cell-1, whereas overexpression of cIAP1 by lentivirus protected against OGD in these cells.
Conclusions—cIAP1 is a shared molecule underlying IP-induced protection in neurons and vascular endothelial cells against HI in the neonatal brain.
- cellular inhibitor of apoptosis 1
- ischemic preconditioning
- neonatal brain
- neurovascular unit
- Received September 19, 2012.
- Revision received September 19, 2012.
- Accepted October 14, 2012.
- © 2012 American Heart Association, Inc.