Specific inhibition of eIF-5A and collagen hydroxylation by a single agent. Antiproliferative and fibrosuppressive effects on smooth muscle cells from human coronary arteries.
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.
McCaffrey
T A
TA
Department of Medicine, Cornell University Medical College, New York Hospital, New York 10021.
Pomerantz
K B
KB
Sanborn
T A
TA
Spokojny
A M
AM
Du
B
B
Park
M H
MH
Folk
J E
JE
Lamberg
A
A
Kivirikko
K I
KI
Falcone
D J
DJ
D000800:Angioplasty, Balloon; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006900:Hydroxylation; D007150:Immunohistochemistry; D008898:Mimosine / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D009183:Mycotoxins / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011347:Procollagen / Q000032:analysis / Q000096:biosynthesis*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000302:isolation & purification; D011753:Pyrones / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification; D018411:Spodoptera; D014162:Transfection; D000097574:Eukaryotic Translation Initiation Factor 5A
D003094:Collagen; D004247:DNA; D008898:Mimosine; D009183:Mycotoxins; D010448:Peptide Initiation Factors; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; D011393:Procollagen-Proline Dioxygenase; D011753:Pyrones; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C011890:kojic acid