Specific inhibition of eIF-5A and collagen hydroxylation by a single agent: Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries
Document Type
Journal Article
Publication Date
1-1-1995
Journal
Journal of Clinical Investigation
Volume
95
Issue
2
DOI
10.1172/JCI117684
Keywords
Cell division; Collagen; Hydroxylases; Mimosine; Vascular smooth muscle
Abstract
Restenosis occurs in 35% of patients within months after balloon angioplasty, due to a fibroproliferative response to vascular injury. These studies describe a combined fibrosuppressive/antiproliferative strategy on smooth muscle cells cultured from human primary atherosclerotic and restenotic coronary arteries and from normal rat aortas. L-Mimosine suppressed the posttranslational hydroxylation of the precursors for collagen and for eukaryotic initiation factor-5A (eIF-5A) by directly inhibiting the specific protein hydroxylases involved, prolyl 4-hydroxylase (E.C. 1.14.11.2) and deoxyhypusyl hydroxylase (E.C. 1.14.99.29), respectively. Inhibition of deoxyhypusyl hydroxylation correlated with a dose-dependent inhibition of DNA synthesis. Inhibition of prolyl hydroxylation caused a dose-dependent reduction in the secretion of hydroxyproline-containing protein and decreased the formation of procollagen types I and III. The antifibroproliferative action could not be attributed to nonspecific or toxic effects of mimosine, appeared to be selective for the hydroxylation step in the biosynthesis of the procollagens and of eIF-5A, and was reversible upon removal of the compound. The strategy of targeting these two protein hydroxylases has important implications for the pathophysiology of restenosis and for the development of agents to control fibroproliferative diseases.
APA Citation
McCaffrey, T., Pomerantz, K., Sanborn, T., Spokojny, A., Du, B., Park, M., Folk, J., Lamberg, A., Kivirikko, K., Falcone, D., Mehta, S., & Hanauske-Abel, H. (1995). Specific inhibition of eIF-5A and collagen hydroxylation by a single agent: Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries. Journal of Clinical Investigation, 95 (2). http://dx.doi.org/10.1172/JCI117684