Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury

Hamid Deliri, Nahum Meller, Ajay Kadakkal, Rohit Malhotra, Jordan Brewster, Amanda C. Doran, Hong Pei, Stephanie N. Oldham, Marcus D. Skaflen, James C. Garmey, Coleen A. McNamara

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Objective- To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury. Methods and results- 12/15LO expression in the vessel wall is increased in animal models of metabolic syndrome and diabetes mellitus. Increased expression of 12/15LO enhances cultured vascular smooth muscle cell (VSMC) proliferation, an effect mediated by the helix-loop-helix factor inhibitor of differentiation 3 (Id3). Carotid endothelial denudation was performed on apolipoprotein (Apo) E, ApoE/12/15LO, C57BL/6, and 12/15LO-overexpressing transgenic mice. ApoE/12/15LO mice had attenuated and 12/15LO-overexpressing transgenic mice had enhanced neointimal formation compared with control mice. 12/15LO-overexpressing transgenic mice had greater postinjury carotid Id3 and Ki-67 expression, cell number, and fibronectin deposition compared with C57BL/6 mice. Loss of 12/15LO attenuated proliferation of cultured ApoE VSMCs, whereas 12/15LO overexpression induced VSMC proliferation. Loss of Id3 enhanced immunoglobulin trascription factor (ITF)-2b binding to and activation of the p21 promoter and abrogated 12/15LO-induced VSMC proliferation. Conclusion- To our knowledge, these data are the first demonstration that increased expression of 12/15LO in the vessel wall enhances Id3-dependent cell proliferation, fibronectin deposition, and neointimal formation in response to injury. Results identify p21 as a potential target of the 12/15LO-Id3 pathway and suggest that modulation of this pathway may have therapeutic implications for targeting the increased risk of restenosis in patients with diabetes.

Original languageEnglish (US)
Pages (from-to)110-116
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • fibronectin
  • helix-loop-helix motifs
  • lipoxygenase neointima
  • smooth muscle cell
  • vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Deliri, H., Meller, N., Kadakkal, A., Malhotra, R., Brewster, J., Doran, A. C., Pei, H., Oldham, S. N., Skaflen, M. D., Garmey, J. C., & McNamara, C. A. (2011). Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury. Arteriosclerosis, thrombosis, and vascular biology, 31(1), 110-116. https://doi.org/10.1161/ATVBAHA.110.212068