Oxygen-dependent diseases in the retina: Role of hypoxia-inducible factors

Abstract

The function of the retina is sensitive to oxygen tension. Any change in the perfusion pressure of the eye affects the retina although the eye is able to autoregulate its hemodynamics. Systemic hypoxemia (lung or heart disease) or a vascular disease in the retina can cause retinal hypoxia. All the hypoxia-dependent events in cells appear to share a common denominator: hypoxia-inducible factor (HIF), which is a heterodimeric transcription factor, a protein. HIF comprises a labile α subunit (1–3), which is regulated, and a stable β subunit, which is constitutively expressed. Both are helix-loop-helix factors and belong to the PAS-domain family of transcription factors. Oxygen plays the key role in stabilizing HIF-1α and its function. When the oxygen tension is normal, HIF-1α is rapidly oxidized by hydroxylase enzymes, but when cells become hypoxic, HIF-1α escapes the degradation and starts to accumulate, triggering the activation of a large number of genes, like vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1α has been shown to have, either clinically or experimentally, a mediating or contributing role in several oxygen-dependent retinal diseases such as von Hippel–Lindau, proliferative diabetic retinopathy, retinopathy of prematurity and glaucoma. In retinitis pigmentosa and high-altitude retinopathy, however, the evidence is still indirect. There are three different strategies available for treating retinal diseases, which have all shown promising results: retinal cell transplantation or replacement, gene replacement, and pharmacological intervention. Specifically, recent results show that the HIF pathway can be used as a therapeutic target, although there is still a long way to go from bench to clinic. HIF can be stabilized by inhibiting prolyl hydroxylase or by blocking the VHL:HIF-α complex if angiogenesis is the goal, as in retinitis pigmentosa. On the other hand, the downregulation of HIF has a pivotal role if we are to inhibit neovascularization, as in proliferative diabetic retinopathy. To date, several small-molecule inhibitors of HIF have been developed and are entering clinical trials. HIF is a remarkable example of a single transcription factor that can be regarded as a “master switch” regulating all the oxygen-dependent retinal diseases.

Introduction

The retina is the most metabolically active tissue in the human body and, therefore, the retina is highly sensitive to reduction in oxygen tension. All animal cells need oxygen for ATP production to fuel metabolic reactions and even the smallest changes in oxygen tension bring about adjustments in order to maintain oxygen homeostasis. Some vertebrate species, such as fish, have adapted to tolerate large variation in ambient oxygen tension during their normal life cycle, an extreme example being the Crucian carp (Carassius carassius), which is able to survive in anoxic conditions for five days without producing damage to heart tissue (Stecyk et al., 2004). Most mammals, including man, however, face serious problems if exposed even for shorter periods of time to low oxygen tension.

We tend to think that the only role for oxygen in cells is to function as an electron acceptor to produce ATP. Recent studies, however, have revealed additional roles for oxygen. Oxygen contributes to the regulation of membrane transport (Gibson et al., 2000), intracellular signaling (Lopez-Barneo et al., 2001), the expression of many genes (Semenza, 2000, Giacca et al., 2004) and the initiation of apoptosis (Carmeliet et al., 1998, Chae et al., 2001). Hypoxia also affects the heart by stimulating the release of atrial natriuretic peptide (ANP) from heart atria (Baertschi et al., 1986, Lew and Baertschi, 1989, Ljusegren and Andersson, 1994, Toth et al., 1994, Focaccio et al., 1995, Ogunyemi et al., 1995, Skvorak et al., 1996, Xu et al., 1996, Klinger et al., 2001). Hence, any disturbance in oxygen tension affects many of the regulatory systems in the human body. Sensing of oxygen not only takes place through the carotid body, but appears to be a property of all tissues (Cherniak, 2004).

Hypoxia is defined as a state in which oxygen tension is below the normal limits found in human tissue beds. Systemic hypoxemia caused by a lung or cardiac disease, and local occlusive vascular diseases in the eye may result in retinal hypoxia. In addition, humans are voluntarily exposed in increasing numbers, for shorter periods of time, to hypoxia at high altitude as mountain trekking has become a popular form of extreme sport. However, many indigenous populations have become permanently acclimatized to living at high altitude with lower oxygen tension.

During the 1990s, it became evident that all the hypoxia-dependent events in cells share a common denominator: hypoxia-inducible factor (HIF). HIF, a transcription factor, was first identified and characterized from human hepatoma cell culture in which the transcription of the hypoxia-inducible erythropoietin gene was mediated by this nuclear factor (Semenza and Wang, 1992). Today we know that HIF is the primary hypoxic signaling protein in cells for regulating angiogenesis and is able to induce the transcription of more than 70 genes (Semenza, 2004). During the present transition from the genomic to a postgenomic era, HIF is a remarkable example of a protein which can be regarded as a “master switch” or “master key” (Semenza, 2000), regulating a wide battery of genes with an astounding array of actions. Although we know that the human hypoxia-inducible factor 1α is expressed by a single gene, HIF1A (Iyer and Leung, 1998), it is the function of the transcription factor which is ruled by oxygen. Here we show how all the oxygen-dependent diseases of the retina are regulated by HIF.