Evidence for 12-lipoxygenase induction in the vessel wall following balloon injury.
OBJECTIVE
Vascular smooth muscle cell (VSMC) migration and proliferation are key events in the development of atherosclerosis and restenosis following angioplasty. These events are mediated by several growth factors and cytokines whose cellular effects include activation of phospholipases and arachidonic acid metabolism via the lipoxygenase (LO) pathway. Since 12-LO products have potent growth and chemotactic effects, we have examined if 12-LO is upregulated in the neointima of injured rat carotid arteries and also if LO inhibition could attenuate neointimal thickening.


METHODS
The left common carotid arteries of male Sprague Dawley rats were injured using a 1.8 F PTCA balloon catheter. Four-fourteen days after injury, injured and uninjured tissue samples were processed for histology, and immunohistochemistry or polymerase chain reaction (PCR) to examine 12-LO expression.


RESULTS
Twelve days after injury, immunohistochemical staining with a 12-LO antibody revealed intense staining in injured left carotid arteries, mainly in neointimal VSMCs and inflammatory cells, but not in the uninjured right arteries. There was also a marked upregulation of 12-LO mRNA (over five-fold by competitive PCR) in the injured arteries. Treatment of the arteries with a LO inhibitor, phenidone, soon after injury resulted in significant inhibition of neointimal thickening. In contrast, a cyclooxygenase inhibitor, ibuprofen, had no effect.


CONCLUSIONS
These results indicate for the first time that balloon injury results in marked induction of 12-LO mRNA and protein expression in the vessel wall. Furthermore, LO pathway activation may mediate, at least in part, the development of the lesion or plaque instability, suggesting a novel target for therapeutic intervention to block these pathological events.
Natarajan
R
R
Department of Diabetes, Endocrinology and Metabolism, Gonda Diabetes Center, City of Hope Medical Center, Duarte, CA 91010, USA. rnatarajan@smtplink.coh.org
Pei
H
H
Gu
J L
JL
Sarma
J M
JM
Nadler
J
J
D000704:Analysis of Variance; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D017536:Carotid Artery, Common; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression; D007150:Immunohistochemistry; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000293:injuries*; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D017539:Tunica Intima / Q000201:enzymology*
D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D001092:Arachidonate 12-Lipoxygenase; C015429:phenidone