title: Profound hypothermia decreases cardiac apoptosis through Akt survival pathway.
abstract: BACKGROUND
  Hypothermia increases the tolerable ischemia time for myocardium in hemorrhagic shock, but precise mechanisms are not clearly established. Here we studied activation of Akt cell survival pathway in a rodent model of emergency preservation and delayed resuscitation.
  
  
  METHODS
  Wistar-Kyoto rats underwent 40% blood volume arterial hemorrhage during 10 minutes and were randomized into 2 groups based on core body temperatures (n = 7/group): hypothermia (15 degrees C) and normothermia (37 degrees C). Hypothermia was induced by infusing cold isotonic solution using cardiopulmonary bypass (CPB) setup. After reaching target body temperature, low-flow state (CPB flow rate of 20 mL/kg/min) was maintained for 60 minutes. Hypothermic rats were rewarmed to baseline temperature; all rats were resuscitated on CPB and monitored for 3 hours. The normothermia group underwent identical CPB management. Sham rats (no hemorrhage, no instrumentation) were used as controls (n = 7). Tissues were harvested at the end of experiment.
  
  
  RESULTS
  Induction of hypothermia increased survival rates (100% versus 0% in normothermia group). Western blot analysis of cardiac tissue revealed increased levels of phospho-Akt (active) in hypothermia and sham groups compared with the normothermia group (p < 0.05). Among downstream targets of Akt, phospho-GSK-3beta (inactive), phospho-Bad (inactive), beta-catenin, and Bcl-2 were considerably elevated in the hypothermia group compared with the normothermia group. Hypothermia also showed decreased activity of caspase-3 protein compared with normothermia (p < 0.05), suggesting decreased apoptosis.
  
  
  CONCLUSIONS
  Profound hypothermia increases survival in a rodent model of hemorrhagic shock and prolonged low-flow state. Hypothermia preserves Akt signaling pathway in cardiomyocytes with a concurrent decrease in cardiac apoptosis.
authors: Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Fahad
authors: F
authors: Shuja
authors: Malek
authors: M
authors: Tabbara
authors: Yongqing
authors: Y
authors: Li
authors: Baoling
authors: B
authors: Liu
authors: Muhammad Umar
authors: MU
authors: Butt
authors: George C
authors: GC
authors: Velmahos
authors: Marc
authors: M
authors: DeMoya
authors: Hasan B
authors: HB
authors: Alam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002315:Cardiopulmonary Bypass; D002470:Cell Survival; D050792:Circulatory Arrest, Deep Hypothermia Induced; D004195:Disease Models, Animal; D008163:Luminescent Measurements; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D051057:Proto-Oncogene Proteins c-akt