Expression of HIF-2α and HIF-3α in the Rat Carotid Body in Chronic Hypoxia

Abstract

Hypoxia is a crucial physiological stimulus in development and plays a key role in the pathophysiology of cancer, stroke, pulmonary disease, and other major causes of mortality (Iyer et al., 1998). Responses to changes in oxygen concentrations are primarily regulated by hypoxia inducible factors (HIFs). HIFs are heterodimeric transcription factors that regulate a number of adaptive responses to low oxygen tension. They are composed of oxygen-regulatedα - and a constitutive non oxygen-regulatedβ - subunits and are belonged to the basic helix-loop-helix-PAS (bHLH-PAS) superfamily (Bruick, 2003). In mammals, three genes have been shown to encode HIF-α subunits namely HIF-1α, -2α and -3 . The HIF-1α protein is more widely expressed, while its homologs, HIF- 2 /Endothelial PAS domain protein (EPAS-1) (Tian et al., 1997) and HIF-3α (Gu et al., 1998) are tissue and developmental specific in their expression. HIF- 1α is expressed in the brain, heart, lung (Jain et al., 1998) and also in the carotid body (CB) (Baby et al., 2003; Tipoe and Fung, 2003). Whereas HIF-2α is expressed in the endothelial cells of various tissues, such as brain, heart, and liver, and the mRNA is also observed in alveolar epithelial cells in the lung (Ema et al., 1997). The EPAS-1 expression in mice embryo was induced by hypoxia for proper cardiac function (Tian et al., 1998). Furthermore, all the HIF- α subunits have been found in the kidney where diverse functions of the three had been shown. HIF-1α and -2α activate the expression of the HIF-mediated gene such as erythropoietin (EPO), whereas HIF-3α is likely an inhibitor of EPO gene transcription (Hara et al., 2001; Jelkmann, 2004).