Increased 12/15-lipoxygenase enhances cell growth, fibronectin deposition, and neointimal formation in response to carotid injury.
OBJECTIVE
To determine whether increased 12/15-lipoxygenase (12/15LO) expression in vivo enhances neointimal formation in response to injury.


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(cip1) promoter and abrogated 12/15LO-induced VSMC proliferation.


CONCLUSIONS
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(cip1) 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.
Deliri
Hamid
H
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22904, USA.
Meller
Nahum
N
Kadakkal
Ajay
A
Malhotra
Rohit
R
Brewster
Jordan
J
Doran
Amanda C
AC
Pei
Hong
H
Oldham
Stephanie N
SN
Skaflen
Marcus D
MD
Garmey
James C
JC
McNamara
Coleen A
CA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001665:Binding Sites; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism*; D006965:Hyperplasia; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D013997:Time Factors; D000073940:Transcription Factor 4; D017539:Tunica Intima / Q000201:enzymology* / Q000473:pathology
C475064:12-15-lipoxygenase; D001057:Apolipoproteins E; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005353:Fibronectins; D051796:Inhibitor of Differentiation Proteins; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; C067679:Idb3 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase