Sirt3 mediates the cardioprotective effect of therapeutic hypothermia after cardiac arrest and resuscitation by restoring autophagic flux via the pi3k/akt/mtor pathway.
Shock (Augusta, Ga.)(2024)
Abstract
ABSTRACT:Background : Postresuscitation cardiac dysfunction is a significant contributor to early death following cardiopulmonary resuscitation (CPR). Therapeutic hypothermia (TH) mitigates myocardial dysfunction due to cardiac arrest (CA); however, the underlying mechanism remains unclear. Sirtuin 3 (Sirt3) was found to affect autophagic activity in recent research, motivating us to investigate its role in the cardioprotective effects of TH in the treatment of CA. Methods : Sprague-Dawley rats were used to establish an in vivo CA/CPR model and treated with a selective Sirt3 inhibitor or vehicle. Survival rate, myocardial function, autophagic flux, and Sirt3 expression and activity were evaluated. H9C2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro . The cells were transfected with Sirt3-siRNA and treated with the autophagy inhibitor chloroquine or the PI3K inhibitor LY294002, and cell viability and autophagic flux were assessed. Results : Rats exhibited decreased survival and impaired cardiac function after CA/CPR, which were alleviated by TH. Mechanistically, TH restored Sirt3 expression and autophagic flux, which were impaired by CA/CPR. Sirt3 inactivation diminished the capacity of TH to restore autophagic flux and partially abolished the improvements in myocardial function and survival. An in vitro study further showed that TH-induced restoration of disrupted autophagic flux by OGD/R was attenuated by pretreatment with Sirt3-siRNA, and this attenuation was partially rescued by the inhibition of PI3K/Akt/mTOR signaling cascades. Conclusions : Sirt3 mediates the cardioprotective effect of TH by restoring autophagic flux via the PI3K/Akt/mTOR pathway. These findings suggest the potential of Sirt3 as a therapeutic target for CA.
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