0225 : Inhibition of mitochondrial permeability transition pore by therapeutic hypothermia after cardiac arrest: involvement of RISK signaling pathway

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• 作者：Vincent Jahandiez¹ ; ^{vjahandiez@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Martin Cour¹ ; Maryline Abrial² ; Joseph Loufouat² ; Laurent Argaud¹ ; Michel Ovize²
• 刊名：Archives of Cardiovascular Diseases Supplements
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：8
• 期：3
• 页码：221
• 全文大小：50 K

文摘

Therapeutic hypothermia (TH) is the sole adjuvant therapy to cardiopulmonary resuscitation able to improve neurologic outcomes in Humans. Resuscitated cardiac arrest (CA) initiates the opening of a mitochondrial mega-canal called permeability transition pore (PTP) jeopardizing cell viability. Activation of reperfusion injury salvage kinase (RISK) pathway inhibits PTP opening. We hypothesized that protective effects of TH involved the RISK pathway and thereby inhibit PTP opening in brain.

Materials and methods

NZW rabbits were subjected to a 15 minute period of asphyxial CA followed by resuscitation and 120 minutes of reperfusion. Five groups of animals (n=4-6/group) were studied: Sham; Control (Ctrl); TH, CA with fast hypothermia induced by external cooling at reperfusion (target temperature: 32°C); NIM: IV bolus, at the onset of reflow, of 2.5 mg/kg NIM811 (a non immunosuppressive derivative of cyclosporine A); TH+NIM, hypothermia and NIM811-treated rabbits. The following measurements were carried out: pupillary response to light, cell damage marker (protein S100β), RISK pathway activation (P-Akt/Akt and P-ERK/ERK ratios) and on isolated mitochondria both calcium retention capacity (CRC, i.e. Ca²⁺ amount required for PTP opening) and respiration.

Results

The characteristics of CA were similar among groups. Pupillary response to light, impaired after CA, was preserved by TH (p<0.05 vs. Ctrl). The increase in S100β protein was prevented by TH (p<0.05 vs. Ctrl). TH improved the CRC (altered, by CA) and the ADP – stimulated mitochondrial respiration (p<0.05 vs Ctrl). CA did not increase P-Akt/Akt whereas P-ERK/ERK was significantly increased in the control group (p<0.05 vs. SHAM). TH significantly enhanced P-Akt/Akt while preventing increase in P-ERK/ERK (p<0.05 vs Ctrl). Similar results were obtained in NIM and TH+NIM groups (p<0.05 vs Ctrl).

Conclusions

In our model, TH promoted activation of Akt and limited CAinduced brain damage by inhibiting PTP.

The author hereby declares no conflict of interest