Specific inhibition of eIF-5A and collagen hydroxylation by a single agent. Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries

T A McCaffrey; K B Pomerantz; T A Sanborn; A M Spokojny; B Du; M H Park; J E Folk; A Lamberg; K I Kivirikko; D J Falcone

doi:10.1172/JCI117684

Specific inhibition of eIF-5A and collagen hydroxylation by a single agent. Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries

J Clin Invest. 1995 Feb;95(2):446-55. doi: 10.1172/JCI117684.

Authors

T A McCaffrey¹, K B Pomerantz, T A Sanborn, A M Spokojny, B Du, M H Park, J E Folk, A Lamberg, K I Kivirikko, D J Falcone, et al.

Affiliation

¹ Department of Medicine, Cornell University Medical College, New York Hospital, New York 10021.

PMID: 7860726
PMCID: PMC295486
DOI: 10.1172/JCI117684

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Angioplasty, Balloon
Animals
Arteriosclerosis / metabolism*
Arteriosclerosis / pathology
Arteriosclerosis / surgery
Cell Division / drug effects
Cell Line
Cells, Cultured
Collagen / antagonists & inhibitors
Collagen / biosynthesis*
Coronary Vessels / cytology
Coronary Vessels / metabolism*
Coronary Vessels / pathology
DNA / biosynthesis
Dose-Response Relationship, Drug
Eukaryotic Translation Initiation Factor 5A
Humans
Hydroxylation
Immunohistochemistry
Mimosine / pharmacology*
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / metabolism*
Muscle, Smooth, Vascular / pathology
Mycotoxins / pharmacology
Peptide Initiation Factors / antagonists & inhibitors*
Plasminogen Activator Inhibitor 1 / metabolism
Procollagen / analysis
Procollagen / biosynthesis*
Procollagen-Proline Dioxygenase / antagonists & inhibitors*
Procollagen-Proline Dioxygenase / biosynthesis
Procollagen-Proline Dioxygenase / isolation & purification
Pyrones / pharmacology*
RNA-Binding Proteins*
Rats
Recombinant Proteins / antagonists & inhibitors
Recombinant Proteins / biosynthesis
Recombinant Proteins / isolation & purification
Spodoptera
Transfection

Substances

Mycotoxins
Peptide Initiation Factors
Plasminogen Activator Inhibitor 1
Procollagen
Pyrones
RNA-Binding Proteins
Recombinant Proteins
Mimosine
kojic acid
Collagen
DNA
Procollagen-Proline Dioxygenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding