ReviewProdeath or prosurvival: Two facets of hypoxia inducible factor-1 in perinatal brain injury
Introduction
Perinatal hypoxic–ischemic injury (HII) is the most important cause of acute mortality and morbidity in newborns (Volpe, 2001). Following HII, approximately 45% of newborns die or have permanent neurological deficits including cerebral palsy and there are currently no effective therapies. In contrast to adult stroke, the neonate exhibits a different response to injury. These age-dependent mechanisms of neuronal death result in differential long term neurological consequences and outcomes.
Hypoxia–inducible factor 1 (HIF-1) is a transcription factor that is a pivotal regulator of oxygen homeostasis. Downstream many HIF-1 target genes play vital roles in developmental and physiological processes, such as angiogenesis, glucose transport, and cell proliferation/survival. Activation of these genes by HIF-1 can lead to either prosurvival or prodeath effects, and as such is important for the development of novel therapeutic interventions. However, before exploring the dichotomy of HIF-1 activation it is important to understand its role in development and perinatal brain injury.
Section snippets
Different vulnerability of developing brain compared with adult brain
Compared with the adult brain, the neonatal brain is different in physiological structure, function, cellular composition and signaling pathway related gene activation and protein expression. Likewise, the response to brain injury is also significantly different compared to the adult. First, the blood–brain barrier (BBB) has been shown to be more permeable to various blood-borne solutes and small lipid-insoluble molecules in the fetal rat brain than in adults (Stewart and Hayakawa, 1994,
HIF-1: regulation of activity and target genes
HIF-1 is the most important factor regulating O2 homeostasis and the cellular response to hypoxia and was purified first by Wang et al. (1995a). It is a heterodimeric transcription factor composed of an oxygen-regulated HIF-1α and a constitutively expressed HIF-1β subunit. During normoxic conditions, the hydroxylation of prolines in the oxygen-dependent degradation domain (ODD) of HIF-1α leads to degradation, while the degradation of HIF-1α can be blocked if oxygen availability is reduced (Fig.
Role of HIF-1 in responses of developing brain to injury
The developing brain needs to effectively adapt to reduced tissue oxygen tension. mRNAs of HIF-1α and HIF-1β are constitutively expressed throughout the normal adult rat (Bergeron et al., 1999, Wiener et al., 1996) and in the embryonic mouse brain (Wang et al., 1995a). HIF-1α is strongly expressed in the normal brain of a fetus with the peak at E19 (Royer et al., 2000). However, HIF-1α protein expression is found in the prenatal and perinatal brain but not in the normal adult brain (Fig. 1).
Prosurvival or prodeath?
HIF-1 is considered as a regulator of both prosurvival and prodeath responses in the central nervous system (Table 2, Fig. 3). As Fig. 3 suggests, both hypoxia and free radicals can activate HIF-1 and the opposing effects of HIF-1α can be attributed to the duration and severity of hypoxia and free radical levels. Mild hypoxia induces adaptive gene expression such as EPO, Glut1 and VEGF, whereas severe or sustained hypoxia HIF-1α can lead to activation of prodeath genes, such as BNIP3, COX2, or
Final remarks
The complex response of the neonatal brain to injury may lie in a profuse and excessive induction of HIF-1 and other molecular factors throughout the brain. There are reports of HIF-1α and other molecular factors equally being inducted in infarcted and non-infarcted hemispheres in the neonatal HII (van den Tweel et al., 2006). Although a plausible interpretation is that molecular mediators alone are not sufficient to induce long-term neuronal damage further studies are needed to examine a
Conclusion
The developmental susceptibility of the brain after hypoxic/ischemic injury is likely to be related to HIF-1α, which plays a pivotal role in the development of injury and in normal brain development. To explore potential targets for further therapeutic intervention a better understanding of HIF-1α function, the importance of its target genes during the developmental stage, and further identification of fundamental differences between the neonate and adult brain is required.
Acknowledgment
This study is partially supported by NIH HD43120 and NIH NS54685 to J.H.Z.
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