Abstract
Proliferation of vascular smooth muscle cells (VSMC) is characteristic of restenosis following balloon angioplasty. We show here that a low concentration of a novel iron chelator, desferri-exochelin 772SM, reversibly arrests the growth of human VSMC in vitro, specifically in G(0)/G(1) and S phases. The lipophilic desferri-exochelin is effective more rapidly and at a 10-fold lower concentration than the nonlipophilic iron chelator deferoxamine. Treatment of growth-synchronized VSMC with the desferri-exochelin results in down-regulation of cyclin E/ Cdk2 and cyclin A/Cdk2 activity but does not affect the cyclin D/Cdk4/retinoblastoma phosphorylation pathway. Both DNA replication and RNA transcription are inhibited in exochelin-treated cells, but protein synthesis is not. The ability of desferri-exochelin 772SM to reversibly block the growth of VSMC in vitro with no apparent cytotoxicity suggests that the exochelin may be useful as a therapeutic agent to limit restenosis in injured vessels.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Aorta
-
CDC2-CDC28 Kinases*
-
Cell Cycle / drug effects*
-
Cell Division / drug effects
-
Cells, Cultured
-
Cyclin E / metabolism
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinases / metabolism
-
Deferoxamine / pharmacology
-
Dose-Response Relationship, Drug
-
Epidermal Growth Factor / pharmacology
-
Ferric Compounds / pharmacology*
-
Humans
-
Iliac Artery
-
Iron Chelating Agents / pharmacology*
-
Kinetics
-
Muscle, Smooth, Vascular / cytology*
-
Muscle, Smooth, Vascular / drug effects
-
Mycobacterium tuberculosis*
-
Peptides, Cyclic / pharmacology*
-
Phosphorylation
-
Protein Serine-Threonine Kinases / metabolism
-
Retinoblastoma Protein / metabolism
-
Saphenous Vein
Substances
-
Cyclin E
-
Ferric Compounds
-
Iron Chelating Agents
-
Peptides, Cyclic
-
Retinoblastoma Protein
-
desferriexochelin 772SM
-
ferriexochelin
-
Epidermal Growth Factor
-
Protein Serine-Threonine Kinases
-
CDC2-CDC28 Kinases
-
CDK2 protein, human
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinases
-
Deferoxamine