Published Online
on June 13, 2005

A more recent version of this article appeared on June 21, 2005

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Submitted on November 15, 2003
Revised on January 20, 2005
Accepted on March 11, 2005

Local Expression of Platelet-Activating Factor-Acetylhydrolase Reduces Accumulation of Oxidized Lipoproteins and Inhibits Inflammation, Shear Stress-Induced Thrombosis, and Neointima Formation in Balloon-Injured Carotid Arteries in Nonhyperlipidemic Rabbits

Hideki Arakawa MD, Jian-Yong Qian MD, PhD, Dolgor Baatar MD, PhD, Ken Karasawa PhD, Yujiro Asada MD, PhD, Yasuyuki Sasaguri MD, PhD, Elizabeth R. Miller BS, Joseph L. Witztum MD, and Hikaru Ueno MD, PhD^*

From the Departments of Biochemistry and Molecular Pathophysiology (H.A., J.Q., D.B., H.U.) and Pathology (Y.S.), University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan; Faculty of Pharmaceutical Science, Teikyo University, Kanagawa, Japan (K.K.); Department of Pathology, Miyazaki Medical College, Miyazaki, Japan (Y.A.); and Department of Medicine, University of California at San Diego, La Jolla (E.R.M., J.L.W.).

^* To whom correspondence should be addressed. E-mail: hueno{at}med.uoeh-u.ac.jp.

Background--Platelet-activating factor (PAF) and PAF-like phospholipids are inactivated by PAF-acetylhydrolase (PAF-AH). Using nonhyperlipidemic animals, we tested whether local expression of PAF-AH into injured arteries might induce antithrombotic and antiinflammatory effects.

Method and Results--Balloon-injured rabbit carotid arteries were infected at the time of injury with an adenovirus expressing either human plasma PAF-AH (AdPAF-AH) or bacterial -galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress-induced thrombosis was observed in all AdLacZ-infected and saline-infused arteries (controls) but eliminated in AdPAF-AH-treated contralateral arteries, even in the presence of epinephrine or an inhibitor of NO production. Injury-induced expression of tissue factor was also significantly suppressed. In AdPAF-AH-treated arteries compared with controls, the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 and macrophage infiltration were decreased by 66%, 66%, and 71%, respectively (P<0.01), and intimal area and intima/media ratio were decreased on day 21 by 43% and 52%, respectively (P<0.05). Within 1 week after injury, oxidized lipoproteins (OxLDL) had readily accumulated in the arterial wall. However, this was markedly reduced in the AdPAF-AH-treated arteries. No differences in the titers of autoantibodies to OxLDL or total cholesterol in blood were found between controls and AdPAF-AH-treated rabbits.

Conclusions--Our results show for the first time that OxLDL accumulates in arteries in nonhyperlipidemic animals within 1 week after injury and that local expression of PAF-AH reduces this accumulation and exerts antiinflammatory, antithrombotic, and antiproliferative effects without changing the plasma levels of PAF-AH activity or titers of autoantibodies to OxLDL.

Key words: gene therapy • inflammation • lipoproteins • thrombosis • platelet activating factor

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