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.
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 beta-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.
Arakawa
Hideki
H
Department of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Qian
Jian-Yong
JY
Baatar
Dolgor
D
Karasawa
Ken
K
Asada
Yujiro
Y
Sasaguri
Yasuyuki
Y
Miller
Elizabeth R
ER
Witztum
Joseph L
JL
Ueno
Hikaru
H
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001323:Autoantibodies / Q000032:analysis; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000150:complications / Q000628:therapy*; D002404:Catheterization / Q000009:adverse effects; D015815:Cell Adhesion Molecules / Q000032:analysis; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D006801:Humans; D007249:Inflammation / Q000517:prevention & control* / Q000628:therapy; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D011817:Rabbits; D013314:Stress, Mechanical; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy; D014161:Transduction, Genetic; D017539:Tunica Intima / Q000254:growth & development*
D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D005343:Fibrinolytic Agents; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase