The effects of ageing on the responses in HIF-1 binding and adrenomedullin gene expression in the rat lung to acute hypoxia

Abstract

Adrenomedullin (AM) may play an important role in the physiological response to hypoxia, particularly in the lung where it may cause bronchiodilation and vasodilation. Hypoxia-induced transcription of the gene coding for AM is regulated by the hypoxia-inducible factor-1 (HIF-1) and recent studies have shown a decrease of HIF-1 protein and its DNA binding activity in old animals. The objective of this study is to find out whether the AM response to acute hypoxia is compromised in the old rats. Male S.D. rats aged 3 months (young), 11–12 months (middle-aged) and 22 months (old) were subjected to acute hypoxia of 8% oxygen for 6 h and the binding of HIF-1 to DNA and the levels and gene expression of AM were measured in the lung and compared with age matched controls. There was an age-related increase in HIF-1 binding to DNA and acute hypoxia led to an increase of this binding in the young and middle-aged but not in the old rats. The preproAM mRNA and AM levels in the lung did not show any age-related difference but the response to acute hypoxia was absent in the old rats. Immunoctytochemical studies of the lung from the young rat demonstrated AM in the epithelial cells of the bronchioles, alveolar cells and also in macrophages. There were increases in plasma AM levels in response to hypoxia in rats of all 3 ages as well as preproAM mRNA levels in other tissues. In conclusion, ageing may affect the response of the AM system in the lung and other tissues in response to acute hypoxia.