Prolonged hypoxia accelerates the posttranscriptional process of collagen synthesis in cultured fibroblasts.

Molecular oxygen is essential for metazoan life. Hypoxia, a reduced oxygen condition, induces systemic and cellular responses for acclimation to the limited oxygen availability. Multicellularity of metazoans is maintained on extracellular matrices. Previously, we demonstrated that acute hypoxia up-regulated the prolyl 4-hydroxylase alpha(I) subunit, the rate-limiting subunit for the hydroxylation of proline residues of procollagens (Y. Takahashi, S. Takahashi, Y. Shiga, T. Yoshimi, and T Miura, 2000, J. Biol. Chem., 275, 14139-14146). The formation of hydroxyproline is an essential posttranscriptional process for stabilization of the helical trimer of procollagen polypeptides at physiological temperature. In this present study, we cultured fetal rat lung fibroblasts for up to 9 days and examined the effects of prolonged hypoxia on the level of procollagen mRNA in the cells and the posttranscriptional steps of collagen synthesis. Hypoxia accelerated the deposition of collagen molecules. These enhancements in hypoxic cultures were observed with or without ascorbic acid in the culture medium. The steady-state level of procollagen alpha1(I) mRNA was not affected by the prolonged hypoxia. In contrast, the mRNA and protein levels of the prolyl 4-hydroxylase alpha(I) subunit were increased by hypoxic culture under both ascorbic acid-sufficient and -deficient conditions. These results suggest that hypoxic enhancement of the posttranscriptional step of collagen synthesis contributed to the accelerated deposition of collagen fibrils.