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Cardiovascular Research 1999 41(2):489-499; doi:10.1016/S0008-6363(98)00312-5
© 1999 by European Society of Cardiology
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Copyright © 1999, European Society of Cardiology

Evidence for 12-lipoxygenase induction in the vessel wall following balloon injury

Rama Natarajana,*, Hong Peia, Jia-Li Gua, Jonnalegedda M. Sarmab,1,1 and Jerry Nadlera

aDepartment of Diabetes, Endocrinology and Metabolism, Gonda Diabetes Center, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
bDepartment of Cardiology, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA

* Corresponding author. Tel.: +626-359-8111, ext 2289; fax: +626-301-8136; e-mail: rnatarajan@smtplink.coh.org

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 1.8F 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.

KEYWORDS Lipid signaling; Lipoxygenase; Balloon angioplasty; Restenosis; Rats; Neointimal thickening; PCR

1 Present address: Department of Cardiology, VA Medical Center, Los Angeles, CA 90073, USA.


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