Identification of protective cellular pathways involved in ischemic preconditioning

Resumen del póster presentado al XXXIX Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Salamanca del 5 al 8 de septiembre de 2016.Ischemic preconditioning (IPC) is one of the most important endogenous mechanisms responsible for the increased tolerance of brain and heart after an ischemic insult. Although the molecular mechanisms underlying IPC-induced cell protection are still unknown, several studies suggest that IPC promotes the activation of endogenous antioxidant systems and modulates apoptosis. Then, IPC is an effective tool for identifying molecular targets involved in cell survival. In this context, two transcription factors, p53 -the key regulator of apoptotic cell death- and the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein -the key regulator of antioxidant response-, have been described to play an essential role in the progression of cerebral ischemia and heart failure. Our work is focused on the study of the role of p53 and Nrf2 on the IPC-induced cell protection against an ischemic insult. Indeed, cellular redox status is directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. For this purpose, we used two different models of IPC insults: i) primary cultured cortical neurons were stimulated with moderate concentrations of N-methyl-D-aspartate (20 μM NMDA); and ii) human endothelial cells were incubated upon sublethal oxygen and glucose deprivation (OGD) conditions for 20 min. After the corresponding IPC insult, cells were incubated for further 2 h either in the presence (IPC) or absence (IPC+OGD) of oxygen and glucose (lethal OGD). Our results show that IPC modulated p53-mediated neuronal apoptosis by interfering with the caspase-3 pathway. IPC prevents the OGD-induced p53 mRNA levels abrogating the accumulation of p53 and its target p21 in cortical neurons.Furthermore, IPC modulated mRNA levels of Nrf2 and its targets hemeoxygenese-1 (HO-1) and NADPH quinona reductase NQO1 in endothelial cells. Our results demonstrate that IPC promotes cell survival through the control of the p53 signaling pathway and the Nrf2-antioxidant pathway. Then, IPC plays a key role in the control of cellular redox homeostasis and survival.Funded by grants from the Instituto de Salud Carlos III (Miguel Servet I CP0014/00010; RD12/0014/0007); FEDER (European regional development fund).Peer reviewe