The evolutionary and physiological significance of the Hif pathway in teleost fishes

The hypoxia-inducible factor (HIF) pathway is a key regulator of cellular O-2 homeostasis and an important orchestrator of the physiological responses to hypoxia (low O-2) in vertebrates. Fish can be exposed to significant and frequent changes in environmental O-2, and increases in Hif-alpha (the hypoxia-sensitive subunit of the transcription factor Hif) have been documented in a number of species as a result of a decrease in O-2. Here, we discuss the impact of the Hif pathway on the hypoxic response and the contribution to hypoxia tolerance, particularly in fishes of the cyprinid lineage, which includes the zebrafish (Danio rerio). The cyprinids are of specific interest because, unlike in most other fishes, duplicated paralogs of the Hif-alpha isoforms arising from a teleost-specific genome duplication event have been retained. Positive selection has acted on the duplicated paralogs of the Hif-alpha isoforms in some cyprinid subfamilies, pointing to adaptive evolutionary change in the paralogs. Thus, cyprinids are valuable models for exploring the evolutionary significance and physiological impact of the Hif pathway on the hypoxic response. Knockout in zebrafish of either paralog of Hif-1 alpha greatly reduces hypoxia tolerance, indicating the importance of both paralogs to the hypoxic response. Here, with an emphasis on the cardiorespiratory system, we focus on the role of Hif-1 alpha in the hypoxic ventilatory response and the regulation of cardiac function. We explore the effects of the duration of the hypoxic exposure (acute, sustained or intermittent) on the impact of Hif-1 alpha on cardiorespiratory function and compare relevant data with those from mammalian systems.