(Circulation. 1996;93:10-17.)
© 1996 American Heart Association, Inc.
Articles |
Prevention of Arterial Thrombosis by Adenovirus-Mediated Transfer of Cyclooxygenase Gene
From The University of Texas–Houston Health Science Center (P.Z., J.M., X.-M.X., D.L.-M., L.M.B., J.T.W., K.K.W.); University of Texas Southwestern Medical School, Dallas (R.S.M.); and Texas Heart Institute, Houston, Tex (F.J.C., L.M.B., J.T.W.).
Correspondence to Kenneth K. Wu, MD, Professor and Director, Division of Hematology, and Vascular Biology Research Center, Department of Medicine, University of Texas–Houston Medical School, 6431 Fannin, MSB 5.016, Houston, TX 77030.
Background Prostacyclin is an important vasoprotective molecule. It inhibits platelet aggregation, monocyte interaction with endothelium, and smooth muscle cell lipid accumulation. Vascular cyclooxygenase-1 (COX-1) is the rate-limiting step in prostacyclin synthesis. The objective of this study was to determine whether adenovirus-mediated transfer of COX-1 could restore COX-1 activity, augment prostacyclin synthesis, and prevent thrombus formation in a porcine carotid angioplasty model.
Methods and Results Human COX-1 cDNA driven by a
cytomegalovirus promoter was constructed into a
replication-defective adenovirus 5 vector by homologous
recombination. Recombinant adenovirus without a foreign gene (Ad-RR)
and buffer were included as controls. Recombinant Ad-LacZ was used for
marking the transfected cells in vivo. In the in vitro experiments,
cultured human endothelial cells (ECs) and porcine
arterial smooth muscle cells (SMCs) were incubated with
Ad-COX-1 for 2 hours and 6-keto-PGF1
level and the
transgene expression were determined 72 hours after infection. In the
in vivo experiments, recombinant adenoviruses were directly instilled
into angioplasty-injured porcine carotid arteries for 30 minutes.
Cyclic flow changes were monitored for 10 days and thrombus formation
was examined histologically thereafter. Transgene
expression and prostaglandin I2
(PGI2) synthesis by the injured arteries were determined.
Cultured ECs infected with Ad-COX-1 produced a fivefold to eightfold
increase in PGI2, and the transgene expression in
cultured porcine SMCs was demonstrated by Northern analysis.
Direct administration of Ad-COX-1 at a dose of 3x1010 pfu
completely inhibited carotid cyclic flow changes and thrombus formation
accompanied by a fourfold increase in PGI2 synthesis by the
injured arteries 10 days after infection, whereas Ad-COX-1 at a lower
dose, 5x109 pfu, had no antithrombotic effects when
compared with Ad-RR vector and buffer controls.
Conclusions Adenovirus-mediated transfer of COX-1 to angioplasty-injured carotid arteries was efficacious in augmenting PGI2 synthesis and was associated with an inhibition of thrombosis when a relatively high titer of adenovirus was instilled.
Key Words: thrombosis • prostaglandins • gene transfer • angioplasty
This article has been cited by other articles:
 |
|
 |
|
  X. Zhao, S. Song, G. Sun, R. Strong, J. Zhang, J. C. Grotta, and J. Aronowski Neuroprotective Role of Haptoglobin after Intracerebral Hemorrhage J. Neurosci., December 16, 2009; 29(50): 15819 - 15827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Yokouchi, Y. Numaguchi, R. Kubota, M. Ishii, H. Imai, R. Murakami, Y. Ogawa, T. Kondo, K. Okumura, D. E. Ingber, et al. l-Caldesmon Regulates Proliferation and Migration of Vascular Smooth Muscle Cells and Inhibits Neointimal Formation After Angioplasty Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2231 - 2237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Tan, S.-A. Xue, M. Manunta, S. C. Beutelspacher, H. Fazekasova, A.K.M. Shamsul Alam, M. O. McClure, and A. J.T. George Effect of Vectors on Human Endothelial Cell Signal Transduction: Implications for Cardiovascular Gene Therapy Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 462 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-N. Lin, W.-M. Cheung, J.-S. Wu, J.-J. Chen, H. Lin, J.-J. Chen, J.-Y. Liou, S.-K. Shyue, and K. K. Wu 15d-Prostaglandin J2 Protects Brain From Ischemia-Reperfusion Injury Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 481 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2592 - H2601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-C. Shyu, S.-Z. Lin, M.-F. Chiang, D.-C. Ding, K.-W. Li, S.-F. Chen, H.-I Yang, and H. Li Overexpression of PrPC by Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model J. Neurosci., September 28, 2005; 25(39): 8967 - 8977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Liu, Z.-Q. Chen, G. C. Bobustuc, J. M. McNatt, H. Segall, S. Pan, J. T. Willerson, and P. Zoldhelyi Local Gene Transduction of Cyclooxygenase-1 Increases Blood Flow in Injured Atherosclerotic Rabbit Arteries Circulation, April 12, 2005; 111(14): 1833 - 1840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Sharif, K. Daly, J. Crowley, and T. O'Brien Current status of catheter- and stent-based gene therapy Cardiovasc Res, November 1, 2004; 64(2): 208 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wen, S. Graf, P. G. Massey, and D. A. Dichek Improved Vascular Gene Transfer With a Helper-Dependent Adenoviral Vector Circulation, September 14, 2004; 110(11): 1484 - 1491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Tulis, Z. H. Mnjoyan, R. L. Schiesser, H. S. Shelat, A. J. Evans, P. Zoldhelyi, and K. Fujise Adenoviral Gene Transfer of Fortilin Attenuates Neointima Formation Through Suppression of Vascular Smooth Muscle Cell Proliferation and Migration Circulation, January 7, 2003; 107(1): 98 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Qian, A. Haruno, Y. Asada, T. Nishida, Y. Saito, T. Matsuda, and H. Ueno Local Expression of C-Type Natriuretic Peptide Suppresses Inflammation, Eliminates Shear Stress-Induced Thrombosis, and Prevents Neointima Formation Through Enhanced Nitric Oxide Production in Rabbit Injured Carotid Arteries Circ. Res., November 29, 2002; 91(11): 1063 - 1069. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Connolly, D. J. Bouchier-Hayes, E. Kaye, A. Leahy, D. Fitzgerald, and O. Belton Cyclooxygenase Isozyme Expression and Intimal Hyperplasia in a Rat Model of Balloon Angioplasty J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 393 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.S. Wung, J.J. Cheng, S.-K. Shyue, and D.L. Wang NO Modulates Monocyte Chemotactic Protein-1 Expression in Endothelial Cells Under Cyclic Strain Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1941 - 1947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Davidge Prostaglandin H Synthase and Vascular Function Circ. Res., October 12, 2001; 89(8): 650 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Golino, P. Cirillo, P. Calabro', M. Ragni, D. D'Andrea, E. V. Avvedimento, F. Vigorito, N. Corcione, F. Loffredo, and M. Chiariello Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries J. Am. Coll. Cardiol., August 1, 2001; 38(2): 569 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-K. Shyue, M.-J. Tsai, J.-Y. Liou, J. T. Willerson, and K. K. Wu Selective Augmentation of Prostacyclin Production by Combined Prostacyclin Synthase and Cyclooxygenase-1 Gene Transfer Circulation, April 24, 2001; 103(16): 2090 - 2095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zoldhelyi, Z.-Q. Chen, H. S. Shelat, J. M. McNatt, and J. T. Willerson Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries PNAS, March 27, 2001; 98(7): 4078 - 4083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori, C. Napolitano, N. Tiso, M. Memmi, G. Vignati, R. Bloise, V. Sorrentino, and G. A. Danieli Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia Circulation, December 6, 2000; (2000) 11. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Waugh, J. Li-Hawkins, E. Yuksel, M. D. Kuo, P. N. Cifra, P. R. Hilfiker, R. Geske, M. Chawla, J. Thomas, S. M. Shenaq, et al. Thrombomodulin Overexpression to Limit Neointima Formation Circulation, July 18, 2000; 102(3): 332 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Y. Liou, S.-K. Shyue, M.-J. Tsai, C.-L. Chung, K.-Y. Chu, and K. K. Wu Colocalization of Prostacyclin Synthase with Prostaglandin H Synthase-1 (PGHS-1) but Not Phorbol Ester-induced PGHS-2 in Cultured Endothelial Cells J. Biol. Chem., May 12, 2000; 275(20): 15314 - 15320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Rentrop Thrombi in Acute Coronary Syndromes : Revisited and Revised Circulation, April 4, 2000; 101(13): 1619 - 1626. [Full Text] [PDF]
|
|
|
|
|
|
P. Zoldhelyi, J. McNatt, H. S. Shelat, Y. Yamamoto, Z.-Q. Chen, and J. T. Willerson Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor Circulation, January 25, 2000; 101(3): 289 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vinals, J. Martinez-Gonzalez, and L. Badimon Regulatory Effects of HDL on Smooth Muscle Cell Prostacyclin Release Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2405 - 2411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Harada, Y. Toki, Y. Numaguchi, H. Osanai, T. Ito, K. Okumura, and T. Hayakawa Prostacyclin synthase gene transfer inhibits neointimal formation in rat balloon-injured arteries without bleeding complications Cardiovasc Res, August 1, 1999; 43(2): 481 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nishida, H. Ueno, N. Atsuchi, R. Kawano, Y. Asada, Y. Nakahara, Y.-i. Kamikubo, A. Takeshita, and H. Yasui Adenovirus-Mediated Local Expression of Human Tissue Factor Pathway Inhibitor Eliminates Shear Stress–Induced Recurrent Thrombosis in the Injured Carotid Artery of the Rabbit Circ. Res., June 25, 1999; 84(12): 1446 - 1452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Massberg, M. Sausbier, P. Klatt, M. Bauer, A. Pfeifer, W. Siess, R. Fassler, P. Ruth, F. Krombach, and F. Hofmann Increased Adhesion and Aggregation of Platelets Lacking Cyclic Guanosine 3',5'-Monophosphate Kinase I J. Exp. Med., April 19, 1999; 189(8): 1255 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Numaguchi, K. Naruse, M. Harada, H. Osanai, S. Mokuno, K. Murase, H. Matsui, Y. Toki, T. Ito, K. Okumura, et al. Prostacyclin Synthase Gene Transfer Accelerates Reendothelialization and Inhibits Neointimal Formation in Rat Carotid Arteries After Balloon Injury Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 727 - 733. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Todaka, C. Yokoyama, H. Yanamoto, N. Hashimoto, I. Nagata, T. Tsukahara, S. Hara, T. Hatae, R. Morishita, M. Aoki, et al. Gene Transfer of Human Prostacyclin Synthase Prevents Neointimal Formation After Carotid Balloon Injury in Rats • Editorial Comment Stroke, February 1, 1999; 30(2): 419 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cheng, G. Mantile, R. Pauly, C. Nater, A. Felici, R. Monticone, C. Bilato, Y. A. Gluzband, M. T. Crow, W. Stetler-Stevenson, et al. Adenovirus-Mediated Gene Transfer of the Human Tissue Inhibitor of Metalloproteinase-2 Blocks Vascular Smooth Muscle Cell Invasiveness In Vitro and Modulates Neointimal Development In Vivo Circulation, November 17, 1998; 98(20): 2195 - 2201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Baek and K. L. March Gene Therapy for Restenosis : Getting Nearer the Heart of the Matter Circ. Res., February 23, 1998; 82(3): 295 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H Baker, D. Mehta, S. J George, and G. D Angelini Prevention of vein graft failure: potential applications for gene therapy Cardiovasc Res, September 1, 1997; 35(3): 442 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D Gerard and D. Collen Adenovirus gene therapy for hypercholesterolemia, thrombosis and restenosis Cardiovasc Res, September 1, 1997; 35(3): 451 - 458. [Full Text] [PDF]
|
|
|
|
|
|
G. Vassalli and D. A Dichek Gene therapy for arterial thrombosis Cardiovasc Res, September 1, 1997; 35(3): 459 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Singh, S. Pan, C. S. Mueske, T. Witt, L. S. Kleppe, T. E. Peterson, A. Slobodova, J.-Y. Chang, N. M. Caplice, and R. D. Simari Role for Tissue Factor Pathway in Murine Model of Vascular Remodeling Circ. Res., July 6, 2001; 89(1): 71 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Burleigh, V. R. Babaev, J. A. Oates, R. C. Harris, S. Gautam, D. Riendeau, L. J. Marnett, J. D. Morrow, S. Fazio, and M. F. Linton Cyclooxygenase-2 Promotes Early Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Circulation, April 16, 2002; 105(15): 1816 - 1823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Lin, T.-N. Lin, W.-M. Cheung, G.-M. Nian, P.-H. Tseng, S.-F. Chen, J.-J. Chen, S.-K. Shyue, J.-Y. Liou, C.-W. Wu, et al. Cyclooxygenase-1 and Bicistronic Cyclooxygenase-1/Prostacyclin Synthase Gene Transfer Protect Against Ischemic Cerebral Infarction Circulation, April 23, 2002; 105(16): 1962 - 1969. [Abstract] [Full Text] [PDF]
|
|