Abstract 19415: Akt1 Deficiency Blocks Hypothermia Protection and Increases Plasma PBEF after Murine Sudden Cardiac Arrest
Introduction: Therapeutic hypothermia protection for cardiovascular resuscitation has been related by us to enhanced nitric oxide generation and attenuated blood PBEF concentrations and related inflammation. Akt1 is a multi-organ regulator of both NOS3 and inflammation. We hypothesized that Akt1 may be critical for therapeutic hypothermia protection after murine sudden cardiac arrest (SCA).
Methods: C57BL6 wild type (WT) and Akt1+/- mice underwent 8 min of KCl-induced SCA and received intra-arrest cooling to 30-32oC at cardiopulmonary resuscitation (CPR) that was maintained until 1 h after CPR. Outcomes included mean arterial pressure (MAP), lactate clearance and 48 h survival. Tissue markers of Akt activation (Western blot phosphorylation of heart Akt, GSK3β and phospholamban) and inflammation (Western blot heart IκBα degradation and blood PBEF) were also measured.
Results: Compared to the WT mice treated with hypothermia, 48 h survival in Akt1+/- mice was significantly decreased (WT 50% n=14 vs. 35% Akt1 group n=10, p < 0.05) with MAP’s falling 30 min after CPR below 60mmHg (versus 70-80mmHg) with increased blood lactate (2.4 ± 0.3 vs. 3.6 ± 0.4 mmol/L, p < 0.05). Concurrently, heart tissue phosphorylation of Akt Thr308, Akt Ser473, GSK3β Ser9 and phospholamban Thr17 decreased. Increased inflammation was evidenced by decreased heart IκBa degradation and a significant, over 5-fold increase in blood PBEF concentrations exceeding 60ng/ml, a level associated with acute heart failure.
Conclusion: Akt1 plays a critical role in mediating hypothermia protection against SCA injury. Strategies that rapidly modulate Akt activation and downstream Akt1-specific effects during CPR warrant further study.
Author Disclosures: J. Li: None. H. Wang: None. S. Chen: None. D.G. Beiser: None. T.L. Vanden Hoek: None.
- © 2014 by American Heart Association, Inc.