Akt1 genetic deficiency limits hypothermia cardioprotection following murine cardiac arrest.
Therapeutic hypothermia (TH) cardioprotection has recently been associated with increased Akt signaling in a rat model of cardiac arrest. However, it is not known whether Akt is required for this beneficial effect of TH. We used a mouse model of cardiac arrest demonstrating TH cardioprotection to study the response of mice deficient in an Akt1 allele. We hypothesized that Akt1 mediates TH cardioprotection and that decreases in Akt1 content would diminish such protection. Adult C57BL/6 wild-type (WT) mice underwent an 8-min cardiac arrest. After 6 min, the mice were randomized to normothermia (WT(NT), 37 degrees C) or TH (WT(TH), 30 degrees C). Following cardiopulmonary resuscitation and the return of spontaneous circulation (ROSC), the animals were hemodynamically monitored for 240 min (R240). At R240, cardiac tissue Akt content and phosphorylation were assayed. Studies were repeated in Akt1 heterozygous (Akt1(+/-)) mice. As a result, baseline characteristics and ROSC rates were equivalent across groups. At R240, WT(TH) mice exhibited lower heart rate, larger stroke volume, and higher cardiac output than WT(NT) animals (P < 0.05). Cardioprotection in WT(TH) at R240 was associated with increased cardiac Akt phosphorylation at Ser473 and Thr308 compared with that in WT(NT) (P < 0.05). TH-associated alterations in Akt phosphorylation, stroke volume, heart rate, and cardiac output were abrogated in Akt1(+/-) animals. In conclusion, TH improves post-ROSC cardiac function and increases Akt phosphorylation in WT, but not Akt1(+/-), mice. The Akt1 isoform appears necessary for TH-mediated cardioprotection.
Beiser
David G
DG
Sect. of Emergency Medicine, 5841 S. Maryland Ave., MC 5068, Chicago, IL 60637, USA. dbeiser@uchicago.edu
Wojcik
Kimberly R
KR
Zhao
Danhong
D
Orbelyan
Gerasim A
GA
Hamann
Kimm J
KJ
Vanden Hoek
Terry L
TL
D000818:Animals; D002302:Cardiac Output / Q000502:physiology*; D005260:Female; D006323:Heart Arrest / Q000150:complications / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology; D007036:Hypothermia, Induced / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology
C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt