Increased prolyl 4-hydroxylase expression and differential regulation of hypoxia-inducible factors in the aged rat brain

1 Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio; and 2 Discovery Translational Medicine, Wyeth Research, Collegeville, Pennsylvania Submitted 10 October 2008 ; accepted in final form 29 April 2009 Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that mediate the adaptive response of mammalian cells and tissues to changes in tissue oxygenation. In the present study, we show an age-dependent decline in cortical HIF-1 accumulation and activation of HIF target genes in response to hypoxia. This inducible response is significantly attenuated in the cerebral cortex of 18-mo-old Fischer 344 rat yet virtually absent in the cerebral cortex of 24-mo-old Fischer 344 rat. This attenuated HIF-1 response had no effect on mRNA upregulation of HIF-independent genes in the aged cortex. We have provided evidence that this absent HIF-1 response is directly correlated with an increase in the expression of the HIF regulatory enzyme, prolyl 4-hydroxylase (PHD). In addition, our study shows that cortical HIF-2 expression in senescent normoxic controls is also significantly greater than that of younger normoxic controls, despite no difference in HIF-2 mRNA levels. The posttranslational regulation of HIF-2 under normoxic conditions seems to be attenuated in the aged rat brain, which is an in vivo demonstration of differential regulation of HIF-1 and HIF-2 . aging; hypoxia; hypoxia inducible factor-1; hypoxia inducible factor-2 Address for reprint requests and other correspondence: J. C. LaManna, Dept. of Physiology & Biophysics, Case Western Reserve Univ., School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4938 (e-mail: joseph.lamanna{at}case.edu )