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《European Journal of Pediatric Surgery》 3:171-177 (2011)

Genetic Suppression of Akt1 Activity Aggravates Cerebral Ischemia/Reperfusion Injury After Deep Hypothermic Low Flow in Transgenic Mice

Ma, Z.; Mo, X.; Yang, Z.; Chen, F.; He, X.

Abstract:

OBJECTIVE: We investigated the genetic role of the PI3K/Akt signaling pathway in Akt1 (+/-) mice after cerebral ischemia/reperfusion injury following post-surgery deep hypothermic low flow. METHODS: 3-week-old Akt1 (+/-) and wild-type C57/B6 mice were randomly and equally divided into sham-surgery and surgery groups. Surgery group mice were subjected to gradual body temperature reduction and bilateral common carotid artery occlusion for 120 min at 18.5 ± 0.5 °C, followed by artery reopening and rewarming. Occlusion was not performed in sham-surgery group animals. Regional cerebral blood flow was determined by laser Doppler flowmetry. Using reverse transcriptase-PCR, apoptotic assays, immunohistology, and Western blot analyses, we determined the apoptotic level of cerebral cells and the expression of Akt signaling pathway components. RESULTS: Regional cerebral blood flow was decreased by ≥ 86% during bilateral common carotid artery occlusion. Akt1 (+/-) mice experienced showed mortality after 24 h of cerebral I/R, and displayed increased numbers of apoptotic cerebral cells and apoptotic protein expression levels. Western analysis revealed Akt1 hypoactivity, which led to less efficient apoptotic signaling pathway inhibition. CONCLUSION: Akt1 suppresses the mitochondrial apoptosis signaling pathway, and Akt1 haplo-insufficiency exacerbates cerebral ischemia/reperfusion after deep hypothermic low flow conditions in mice. Akt may be a potential molecular therapeutic target for brain protection during surgery in congenital heart disease patients.