Epothilone D, a microtubule-stabilizing compound, inhibits neointimal hyperplasia after rat carotid artery injury by cell cycle arrest via regulation of G1-checkpoint proteins

Vascul Pharmacol. 2007 Oct;47(4):229-37. doi: 10.1016/j.vph.2007.06.009. Epub 2007 Jul 5.

Abstract

Epothilone D (Epo-D) is a paclitaxel-like microtubule-stabilizing agent that was isolated from the myxobacterium Sorangium cellulosum. Although Epo-D can inhibit proliferation in multiple tumor cell lines, the effect of Epo-D on neointimal hyperplasia after angioplasty has not been reported. The aim of the present study was to investigate the effects of Epo-D on neointimal hyperplasia using an in vivo rat carotid artery injury model. We demonstrated that local Epo-D treatment significantly reduced neointimal hyperplasia after in vivo rat carotid artery injury, and Epo-D potently inhibited DNA synthesis, cell cycle progression and cell proliferation after FBS- and PDGF-BB-stimulation; PDGF-BB has been identified as the most potent growth factor for stimulating the proliferation of activated rat aortic smooth muscle cells (RASMCs). To clarify the specific effects of Epo-D on cell cycle machinery, we examined its effects on cyclin-dependent kinase (CDK)2, CDK4, cyclin E, p27, and retinoblastoma (Rb) proteins as cell cycle-related proteins in cellular lysates from PDGF-BB-stimulated RASMCs. Epo-D treatment significantly decreased the level of CDK2 protein, but did not change the levels of CDK4 and cyclin E proteins. Furthermore, Epo-D inhibited the phosphorylation of Rb, a key regulator of the G1 to S phase transition in the cell cycle. These findings suggest that Epo-D may regulate the cell cycle G1-checkpoint proteins as its major molecular mechanism for inhibiting neointimal hyperplasia after in vivo rat carotid artery injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • Carotid Artery Injuries / drug therapy*
  • Carotid Artery Injuries / pathology
  • Cyclin-Dependent Kinase 2 / analysis
  • Cyclin-Dependent Kinase 4 / analysis
  • Epothilones / pharmacology*
  • G1 Phase / drug effects*
  • Hyperplasia
  • Male
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / pathology
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis
  • Rats
  • Rats, Sprague-Dawley
  • Thymidine / metabolism
  • Tunica Intima / drug effects*
  • Tunica Intima / pathology

Substances

  • Epothilones
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Becaplermin
  • Cdk2 protein, rat
  • Cdk4 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • desoxyepothilone B
  • Thymidine