(Circulation. 2001;103:2495.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Adenovirus-Mediated Gene Transfer of Human Platelet-Activating Factor–Acetylhydrolase Prevents Injury-Induced Neointima Formation and Reduces Spontaneous Atherosclerosis in Apolipoprotein E–Deficient Mice
From the Center for Molecular and Vascular Biology (R.Q., B.D.G., A.M., M.L., G.T., D.C., P.H.), the Department of Experimental Surgery and Anesthesiology (R.Q., A.M., M.L., P.H.), and the Department of Molecular Cell Biology, Division of Pharmacology (P.V.V.), Katholieke Universiteit Leuven, Leuven, Belgium; INSERM U525, Institut Fédératif "Muscle Coeur et Vaisseaux," Faculté de Médecine Pitié-Salpétrière, Université Pierre et Marie Curie, Paris, France (D.S., E.N.); Laboratoire de Biochimie et de Biologie Cellulaire, FUNDP, Namur, Belgium (C.M., M.R.); and the Department of Pharmacology, University of Antwerpen, Antwerpen, Belgium (H.B.).
Correspondence to Dr P. Holvoet, Department of Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Campus Gasthuisberg O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be
Background—Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E–deficient mice.
Methods and Results—Intravenous administration of an adenovirus (5x108 plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 (P<0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively (P<0.001 for both). Non-HDL and HDL cholesterol levels in PAF-AH–treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins by 82% (P<0.001), macrophages by 69% (P=0.006), and smooth muscle cells by 84% (P=0.002) in the arterial wall. This resulted in a 77% reduction (P<0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed. PAF-AH gene transfer reduced atherosclerotic lesions by 42% (P=0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice (P=0.01 and P=0.04, respectively).
Conclusions—Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E–deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.
Key Words: atherosclerosis • lipoproteins • restenosis
This article has been cited by other articles:
 |
|
 |
|
  A. A. Gardner, E. C. Reichert, M. K. Topham, and D. M. Stafforini Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein J. Biol. Chem., June 20, 2008; 283(25): 17099 - 17106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-L. Levonen, E. Vahakangas, J. K. Koponen, and S. Yla-Herttuala Antioxidant Gene Therapy for Cardiovascular Disease: Current Status and Future Perspectives Circulation, April 22, 2008; 117(16): 2142 - 2150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kono, T. Inoue, Y. Yoshida, H. Sato, T. Matsusue, H. Itabe, E. Niki, J. Aoki, and H. Arai Protection against Oxidative Stress-induced Hepatic Injury by Intracellular Type II Platelet-activating Factor Acetylhydrolase by Metabolism of Oxidized Phospholipids in Vivo J. Biol. Chem., January 18, 2008; 283(3): 1628 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Van Eck, M. Hoekstra, R. B. Hildebrand, Y. Yaong, D. Stengel, J. K. Kruijt, W. Sattler, U. J.F. Tietge, E. Ninio, T. J.C. Van Berkel, et al. Increased Oxidative Stress in Scavenger Receptor BI Knockout Mice With Dysfunctional HDL Arterioscler. Thromb. Vasc. Biol., November 1, 2007; 27(11): 2413 - 2419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, L. D. Tsironis, and A. D. Tselepis New Insights Into the Role of Lipoprotein(a)-Associated Lipoprotein-Associated Phospholipase A2 in Atherosclerosis and Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2094 - 2099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lattin, D. A. Zidar, K. Schroder, S. Kellie, D. A. Hume, and M. J. Sweet G-protein-coupled receptor expression, function, and signaling in macrophages J. Leukoc. Biol., July 1, 2007; 82(1): 16 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Ng, N. Bourquard, S. Y. Hama, D. Shih, V. R. Grijalva, M. Navab, A. M. Fogelman, and S. T. Reddy Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1368 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Mackness, R. Quarck, W. Verreth, M. Mackness, and P. Holvoet Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome Arterioscler. Thromb. Vasc. Biol., July 1, 2006; 26(7): 1545 - 1550. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O'Donoghue, D. A. Morrow, M. S. Sabatine, S. A. Murphy, C. H. McCabe, C. P. Cannon, and E. Braunwald Lipoprotein-Associated Phospholipase A2 and Its Association With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) Trial Circulation, April 11, 2006; 113(14): 1745 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Stafforini, J. R. Sheller, T. S. Blackwell, A. Sapirstein, F. E. Yull, T. M. McIntyre, J. V. Bonventre, S. M. Prescott, and L. J. Roberts II Release of Free F2-isoprostanes from Esterified Phospholipids Is Catalyzed by Intracellular and Plasma Platelet-activating Factor Acetylhydrolases J. Biol. Chem., February 24, 2006; 281(8): 4616 - 4623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Arakawa, J.-Y. Qian, D. Baatar, K. Karasawa, Y. Asada, Y. Sasaguri, E. R. Miller, J. L. Witztum, and H. Ueno 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 Circulation, June 21, 2005; 111(24): 3302 - 3309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sudhir Lipoprotein-Associated Phospholipase A2, a Novel Inflammatory Biomarker and Independent Risk Predictor for Cardiovascular Disease J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3100 - 3105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Zalewski and C. Macphee Role of Lipoprotein-Associated Phospholipase A2 in Atherosclerosis: Biology, Epidemiology, and Possible Therapeutic Target Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 923 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, M. Spite, J. O. Trent, M. B. West, Y. Ahmed, and A. Bhatnagar Aldose Reductase-catalyzed Reduction of Aldehyde Phospholipids J. Biol. Chem., December 17, 2004; 279(51): 53395 - 53406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Shi, H. Pei, J. J. Fischer, J. C. James, J. F. Angle, A. H. Matsumoto, G. A. Helm, and I. J. Sarembock Neointimal formation in two apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility J. Lipid Res., November 1, 2004; 45(11): 2008 - 2014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Ribas, J. L. Sanchez-Quesada, R. Anton, M. Camacho, J. Julve, J. C. Escola-Gil, L. Vila, J. Ordonez-Llanos, and F. Blanco-Vaca Human Apolipoprotein A-II Enrichment Displaces Paraoxonase From HDL and Impairs Its Antioxidant Properties: A New Mechanism Linking HDL Protein Composition and Antiatherogenic Potential Circ. Res., October 15, 2004; 95(8): 789 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Choudhury, J. X. Rong, E. Trogan, V. I. Elmalem, H. M. Dansky, J. L. Breslow, J. L. Witztum, J. T. Fallon, and E. A. Fisher High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions Without Suppressing Indices of Inflammation or Oxidation Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1904 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wu, G. A. Zimmerman, S. M. Prescott, and D. M. Stafforini The p38 MAPK Pathway Mediates Transcriptional Activation of the Plasma Platelet-activating Factor Acetylhydrolase Gene in Macrophages Stimulated with Lipopolysaccharide J. Biol. Chem., August 20, 2004; 279(34): 36158 - 36165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Llodra, V. Angeli, J. Liu, E. Trogan, E. A. Fisher, and G. J. Randolph From the Cover: Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques PNAS, August 10, 2004; 101(32): 11779 - 11784. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ninio, D. Tregouet, J.-L. Carrier, D. Stengel, C. Bickel, C. Perret, H. J. Rupprecht, F. Cambien, S. Blankenberg, and L. Tiret Platelet-activating factor-acetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease Hum. Mol. Genet., July 1, 2004; 13(13): 1341 - 1351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lie, R. de Crom, T. van Gent, R. van Haperen, L. Scheek, F. Sadeghi-Niaraki, and A. van Tol Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins J. Lipid Res., May 1, 2004; 45(5): 805 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kontush, E. C. de Faria, S. Chantepie, and M. J. Chapman Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 526 - 533. [Abstract] [Full Text]
|
|
|
|
|
|
S. Blankenberg, D. Stengel, H. J. Rupprecht, C. Bickel, J. Meyer, F. Cambien, L. Tiret, and E. Ninio Plasma PAF-acetylhydrolase in patients with coronary artery disease: results of a cross-sectional analysis J. Lipid Res., July 1, 2003; 44(7): 1381 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Tsimihodimos, A. Kakafika, A. P. Tambaki, E. Bairaktari, M. J. Chapman, M. Elisaf, and A. D. Tselepis Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins J. Lipid Res., May 1, 2003; 44(5): 927 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Noto, M. Hara, K. Karasawa, N. Iso-O, H. Satoh, M. Togo, Y. Hashimoto, Y. Yamada, T. Kosaka, M. Kawamura, et al. Human Plasma Platelet-Activating Factor Acetylhydrolase Binds to All the Murine Lipoproteins, Conferring Protection Against Oxidative Stress Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 829 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-R. Han, A. Momeni, K. Strach, P. Suriyaphol, D. Fenske, K. Paprotka, S. I. Hashimoto, M. Torzewski, S. Bhakdi, and M. Husmann Enzymatically Modified LDL Induces Cathepsin H in Human Monocytes: Potential Relevance in Early Atherogenesis Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 661 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mertens, P. Verhamme, J. K. Bielicki, M. C. Phillips, R. Quarck, W. Verreth, D. Stengel, E. Ninio, M. Navab, B. Mackness, et al. Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice: LCAT Gene Transfer Decreases Atherosclerosis Circulation, April 1, 2003; 107(12): 1640 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Platelet-activating Factor Acetylhydrolase, and Not Paraoxonase-1, Is the Oxidized Phospholipid Hydrolase of High Density Lipoprotein Particles J. Biol. Chem., January 31, 2003; 278(6): 3937 - 3947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Ng, G. F. Maguire, J. Wylie, A. Ravandi, W. Xuan, Z. Ahmed, M. Eskandarian, A. Kuksis, and P. W. Connelly Oxidative Stress Is Markedly Elevated in Lecithin:Cholesterol Acyltransferase-deficient Mice and Is Paradoxically Reversed in the Apolipoprotein E Knockout Background in Association with a Reduction in Atherosclerosis J. Biol. Chem., March 29, 2002; 277(14): 11715 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Tsimihodimos, S.-A. P. Karabina, A. P. Tambaki, E. Bairaktari, J. A. Goudevenos, M. J. Chapman, M. Elisaf, and A. D. Tselepis Atorvastatin Preferentially Reduces LDL-Associated Platelet-Activating Factor Acetylhydrolase Activity in Dyslipidemias of Type IIA and Type IIB Arterioscler. Thromb. Vasc. Biol., February 1, 2002; 22(2): 306 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, et al. Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1977 - 1983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Tselepis, S.-A. P. Karabina, D. Stengel, R. Piedagnel, M. J. Chapman, and E. Ninio N-linked glycosylation of macrophage-derived PAF-AH is a major determinant of enzyme association with plasma HDL J. Lipid Res., October 1, 2001; 42(10): 1645 - 1654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]
|
|