Triiodothyronine Prevents Cardiac Ischemia/Reperfusion Mitochondrial Impairment and Cell Loss by Regulating miR30a/p53 Axis

Mitochondrial dysfunctions critically affect cardiomyocyte survival during ischemia/reperfusion(I/R) injury. In this scenario p53 activates multiple signaling pathways that impair cardiac mitochondriaand promote cell death. p53 is a validated target of miR-30 whose levels fall underischemic conditions. Although triiodothyronine (T3) rescues post-ischemic mitochondrial activityand cell viability, no data are available on its role in the modulation of p53 signaling in I/R. Herewe test the hypothesis that early T3 supplementation in rats inhibits the post I/R activation of p53pro-death cascade through the maintenance of miRNA 30a expression.In our model, T3 infusion improves the recovery of post-ischemic cardiac performance. At themolecular level, the beneficial effect of T3 is associated with restored levels of miR-30a expressionin the area at risk (AAR) that correspond to p53 mRNA downregulation. The concomitant decreasein p53 protein content reduces Bax expression and limits mitochondrial membrane depolarizationresulting in preserved mitochondrial function and decreased apoptosis and necrosis extent in theAAR. Also in primary cardiomyocyte culture of neonatal rats, T3 prevents both miR-30a downregulationand p53 raise induced by hypoxia. The regulatory effect of T3 is greatly suppressed bymiR-30a knockdown. Overall these data suggest a new mechanism of T3-mediated cardioprotectionthat is targeted to mitochondria and acts, at least in part, through the regulation of miR-30a/p53 axis.