Role of HIF-1a in regulating autophagic cell survival during cerebral ischemia reperfusion in rats.

Abstract

Hypoxia-inducible factor-1a (HIF-1a) plays a beneficial role during cerebral ischemia reperfusion (IR), but the underlying molecular mechanisms are not completely understood. Here, we aimed to investigate the effects and molecular regulation of HIF-1a on brain cell apoptosis and autophagy during IR. We found that augmentation of HIF-1a in re-perfused hematopoietic cells significantly reduced brain damage, alleviated brain edema and improved neural function during IR, seemingly through two HIF-1a target genes BNIP3 and NIX, which were critical regulators for cell apoptosis and autophagic cell survival. in vitro, HIF-1a induced up-regulation of BNIP3 and NIX in human cortical neuron cells, HCN-1A. Inhibition of BNIP3 and NIX significantly attenuated HIF-1a-suppressed cell apoptosis and HIF-1a-induced cell autophagy. Together, these data suggest that HIF-1a may ameliorate brain damages during IR through BNIP3 and NIX -dependent augmentation of autophagic cell survival and reduction in cell apoptosis.