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Indirubin-3'-monoxime blocks vascular smooth muscle cell proliferation by inhibition of signal transducer and activator of transcription 3 signaling and reduces neointima formation in vivo.

AbstractOBJECTIVE:
Our goal was to examine the influence of indirubin-3'-monoxime (I3MO), a natural product-derived cyclin-dependent kinase inhibitor, on vascular smooth muscle cell (VSMC) proliferation in vitro, experimentally induced neointima formation in vivo, and related cell signaling pathways.
METHODS AND RESULTS:
I3MO dose-dependently inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation by arresting cells in the G(0)/G(1) phase of the cell cycle as assessed by 5-bromo-2'-deoxyuridine incorporation and flow cytometry. PDGF-induced activation of the kinases Akt, Erk1/2, and p38(MAPK) was not affected. In contrast, I3MO specifically blocked PDGF-, interferon-γ-, and thrombin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Human endothelial cells (EA.hy926) responded to I3MO with increased endothelial nitric oxide synthase activity as assessed via [(14)C]l-arginine/[(14)C]l-citrulline conversion. The specific STAT3 inhibitor Stattic led to decreased VSMC proliferation, and transient expression of a constitutively active form of STAT3 overcame the I3MO-induced cell cycle arrest in mouse embryonic fibroblasts. In a murine femoral artery cuff model, I3MO prevented neointima formation while reducing STAT3 phosphorylation and the amount of proliferating Ki67-positive cells.
CONCLUSIONS:
I3MO represses PDGF- and thrombin-induced VSMC proliferation and, in vivo, neointima formation, likely because it specifically blocks STAT3 signaling. This profile and its positive effect on endothelial NO production turns I3MO into a promising lead compound to prevent restenosis.
AuthorsAndrea V Schwaiberger, Elke H Heiss, Muris Cabaravdic, Tina Oberan, Jan Zaujec, Daniel Schachner, Pavel Uhrin, Atanas G Atanasov, Johannes M Breuss, Bernd R Binder, Verena M Dirsch
JournalArteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 30 Issue 12 Pg. 2475-81 (Dec 2010) ISSN: 1524-4636 [Electronic] United States
PMID20847306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Indoles
  • Ki-67 Antigen
  • Oximes
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Stat3 protein, rat
  • indirubin-3'-monoxime
  • Becaplermin
  • Interferon-gamma
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Thrombin
Topics
  • Animals
  • Arterial Occlusive Diseases (metabolism, pathology, prevention & control)
  • Becaplermin
  • Cell Cycle (drug effects)
  • Cell Proliferation
  • Cells, Cultured
  • Constriction, Pathologic
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelial Cells (drug effects, metabolism)
  • Femoral Artery (drug effects, metabolism, pathology)
  • Flow Cytometry
  • Humans
  • Hyperplasia
  • Indoles (pharmacology)
  • Interferon-gamma (metabolism)
  • Ki-67 Antigen (metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases (metabolism)
  • Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
  • Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
  • Oximes (pharmacology)
  • Phosphorylation
  • Platelet-Derived Growth Factor (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Proto-Oncogene Proteins c-sis
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
  • Signal Transduction (drug effects)
  • Thrombin (metabolism)
  • Time Factors
  • Transfection

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