Profound hypothermia decreases cardiac apoptosis through Akt survival pathway.
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.
Shuja
Fahad
F
Division of Trauma, Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
Tabbara
Malek
M
Li
Yongqing
Y
Liu
Baoling
B
Butt
Muhammad Umar
MU
Velmahos
George C
GC
DeMoya
Marc
M
Alam
Hasan B
HB
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
D051057:Proto-Oncogene Proteins c-akt