Abstract 12751: Activation of Stat-3 Mitochondria Translocation and Ameliorating Complex I Damage under Hypothermia Treatment for Post-cardiac Arrest Myocardial Dysfunction
Background: Myocardial dysfunction is one of the major causes leading mortality in the post-cardiac arrest period. Hypothermia treatment can ameliorate the myocardial injuries and improve myocardial dysfunction in addition to brain injury. The mechanisms, including the critical pathways and targets are not clearly elucidated. It is found recently that STAT-3, which is identified as a transcription factor, can be also translocated to mitochondria and induce protective effects.
Aims: To investigate the role of STAT-3 and mitochondria complexes in myocardial protection under hypothermia treatment for post-cardiac arrest.
Methods: Rats were resuscitated after 8.5 mins asphyxia-induced cardiac arrest. Hypothermia treatment was initiated after ROSC and targeted at 32oC. H9C2 cardiomyocytes were cultured with simulated ischemia-reperfusion injuries for in vitro study.
Results: The post-cardiac arrest myocardial functions, including cardiac output, left ventricular systolic (dP/dt40) and diastolic function (maximal negative dP/dt) were better in hypothermia treatment group compared to normothermia group at 4 hrs after ROSC (P≤ 0.01, respectively). The mitochondria integrity was more preserved in hypothermia treatment group with less mitochondria permeability transition pore (mPTP) opening and less mitochondria swelling in electronic microscopy at 2 hrs after ROSC (mitochondria damage score 1.13±0.52 vs.0.40±0.50, P≤0.01). The mitochondria translocation of STAT-3 was more significant in hypothermia treatment group. The mitochondria complex I was less injuried while the complexes II and IV had similar severity of damage between hypothermia and normothermia treatment group after cardiac arrest. By using the STAT-3 inhibitor (s3i-201) in simulated ischemia- reperfusion H9c2 cardiomyocyte injury, the hypothermia-induced cytoprotective effect was blocked in a dose-response manner (MTT test 0.71±0.10 without inhibitor vs. 0.45±0.16 in 20um s3i-201, P≤0.01).
Conclusion: Mitochondria translocation of STAT-3 and mitochondria integrity has critical role for the hypothermia [[Unable to Display Character: –]]induced cardiac protection. Modulation of STAT-3 pathway could ameliorate the post-cardiac arrest myocardial dysfunction.
- © 2013 by American Heart Association, Inc.