Age-dependent increase of prolyl-4-hydroxylase domain (PHD) 3 expression in human and mouse heart.
The hypoxia-inducible factor (HIF)-1 is a master transcriptional activator of oxygen-regulated genes involved in energy metabolism, angiogenesis, and erythropoiesis. HIF-1 is composed of the two subunits HIF-1alpha and HIF-1beta (also called ARNT). The destruction of HIF-1alpha in the presence of oxygen is initiated by prolyl-4-hydroxylation. In human cells three closely related prolyl hydroxylases (PHDs) have been identified. An age-dependent decrease in HIF-1alpha expression was reported previously in brain, liver and kidney, which may be associated with a reduced adaptation to hypoxia as found in aged animals and humans. We have determined the expression of HIF-1alpha and the PHDs in human atrial trabeculae under normoxic and hypoxic conditions, in samples of human left ventricles as well as in heart extracts from female mice of different age (5 up to 16 months). With increasing age we found a decreased expression of HIF-1alpha, which correlated to an increased PHD3 expression in mouse and human heart. PHD3 was the most prominent HIF modifying hydroxylase found in human heart samples. Additionally, we found a strong ischemia/hypoxia-inducibility of PHD3 compared to PHD1 and PHD2 in atrial trabeculae. These data may explain the previously reported reduction of HIF-1alpha and HIF-1 target genes such as the vascular endothelial growth factor in ageing tissue.
Rohrbach
Susanne
S
Institute of Pathophysiology, Martin-Luther University Halle, Germany.
Simm
Andreas
A
Pregla
Reinhard
R
Franke
Corinna
C
Katschinski
Dörthe M
DM
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000818:Animals; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D049308:Dioxygenases; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases