Abstract W P111: Early At1 Blockade Ameliorates Ischemia/reperfusion Injury By Pi3k/akt And Enos Pathways: In Vivo And In Vitro Evidence
Background & Objective: We have recently shown a robust protection with Angiotensin (Ang) II type 1 receptor blockers (ARBs) against cerebral ischemia/reperfusion (I/R) injury. However, the mechanisms by which ARBs protect against I/R injury are still unclear. We tested the hypothesis that the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway mediates some of the protective effects of ARBs after I/R injury.
Methods: Male Wistar rats (280-300 g) underwent transient middle cerebral artery occlusion (MCAO) for 90min followed by reperfusion and received intravenous injection of candesartan (1 mg/kg) or vehicle at the time of reperfusion. Additional four groups of candesartan were injected intracerebroventricularly with PI3K/Akt, MEK and p38MAPK inhibitors at 15 min before MCAO. Rats were sacrificed at 24h post-MCAO and brains perfused for evaluation of neurological deficits, infarct size, and protein expression. Oxygen and glucose deprivation/reoxygenation (OGD/R) was used to mimic ischemic insult in hippocampal neuronal cells (HT22).
Results (Table): Candesartan reduced infarct size and improved neurobehavioral outcomes in rats subjected to I/R. Candesartan alone increased phosphorylated eNOS, Akt and VEGF expression after I/R injury. Moreover, blockade of PI3K but not MEK or p28MAPK activity, compromised candesartan-induced protection. These findings provided the first evidence that candesartan improves eNOS phosphorylation in response to the activated PI3K/Akt signaling. In vitro studies further confirmed that candesartan protects against OGD/R-induced neuronal death through PI3K/Akt signaling stimulation in HT-22 cells.
Conclusions: Our findings lead us to suggest that the PI3K/Akt pathway can play a role in mediating the protective effects of candesartan and provide therapeutic avenues for the treatment of stroke.
Author Disclosures: T. Ishrat: None. B. Pillai: None. P.R. Somanath: None. A. Ergul: None. S.C. Fagan: Consultant/Advisory Board; Modest; A consultant for and has received funding from Pfizer..
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate – Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico, Tennessee, U.S. Virgin Islands.
- © 2015 by American Heart Association, Inc.