© 1999 American Heart Association, Inc.
Original Contribution |
Gene Transfer of Endothelial Nitric Oxide Synthase to the Lung of the Mouse In Vivo
Effect on Agonist-Induced and Flow-Mediated Vascular Responses
From the Departments of Pharmacology (H.C.C., T.J.B., A.L.H., P.J.K.), Anatomy (F.M.D'S., J.R.J.), and Medicine (L.A.O.), Tulane University School of Medicine, New Orleans, La, and Departments of Internal Medicine and Pharmacology (K.T., D.D.H.), University of Iowa College of Medicine, Iowa City, Iowa.
Correspondence to Philip J. Kadowitz, Department of Pharmacology SL83, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112. E-mail champion{at}mailhost.tcs.tulane.edu
Abstract—The effects of transfer of the endothelial nitric oxide synthase (eNOS) gene to the lung were studied in mice. After intratracheal administration of AdCMVßgal, expression of the ß-galactosidase reporter gene was detected in pulmonary airway cells, in alveolar cells, and in small pulmonary arteries. Gene expression with AdCMVßgal peaked 1 day after administration and decayed over a 7- to 14-day period, whereas gene expression after AdRSVßgal transfection peaked on day 5 and was sustained over a 21- to 28-day period. One day after administration of AdCMVeNOS, eNOS protein levels were increased, and there was a small reduction in mean pulmonary arterial pressure and pulmonary vascular resistance. The pressure-flow relationship in the pulmonary vascular bed was shifted to the right in animals transfected with eNOS, and pulmonary vasodepressor responses to bradykinin and the type V cGMP-selective phosphodiesterase inhibitor zaprinast were enhanced, whereas systemic responses were not altered. Pulmonary vasopressor responses to endothelin-1 (ET-1), angiotensin II, and ventilatory hypoxia were reduced significantly in animals transfected with the eNOS gene, whereas pressor responses to norepinephrine and U46619 were not changed. Systemic pressor responses to ET-1 and angiotensin II were similar in eNOS-transfected mice and in control mice. Intratracheal administration of AdRSVeNOS attenuated the increase in pulmonary arterial pressure in mice exposed to the fibrogenic anticancer agent bleomycin. These data suggest that transfer of the eNOS gene in vivo can selectively reduce pulmonary vascular resistance and pulmonary pressor responses to ET-1, angiotensin II, and hypoxia; enhance pulmonary depressor responses; and attenuate pulmonary hypertension induced by bleomycin. Moreover, these data suggest that in vivo gene transfer may be a useful therapeutic intervention for the treatment of pulmonary hypertensive disorders.
Key Words: gene transfer • in vivo • pulmonary vascular bed • mouse • nitric oxide
This article has been cited by other articles:
 |
|
 |
|
  X. Wang, H. Chai, P. H. Lin, Q. Yao, and C. Chen Roles and Mechanisms of Human Immunodeficiency Virus Protease Inhibitor Ritonavir and Other Anti-Human Immunodeficiency Virus Drugs in Endothelial Dysfunction of Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells Am. J. Pathol., March 1, 2009; 174(3): 771 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B Wojciak-Stothard New drug targets for pulmonary hypertension: Rho GTPases in pulmonary vascular remodelling Postgrad. Med. J., July 1, 2008; 84(993): 348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhang, S. Wu, X. Lu, M. Wang, and M. Liu Gene Transfer of Endothelial Nitric Oxide Synthase Attenuates Flow-Induced Pulmonary Hypertension in Rabbits Ann. Thorac. Surg., February 1, 2008; 85(2): 581 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Hemnes, A. Zaiman, and H. C. Champion PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L24 - L33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pokreisz, G. Marsboom, and S. Janssens Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension: the right heart revisited Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H75 - H84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Liu, H. Liu, G. Visner, and B. S. Fletcher Sleeping Beauty-mediated eNOS gene therapy attenuates monocrotaline-induced pulmonary hypertension in rats FASEB J, December 1, 2006; 20(14): 2594 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Satoh, Y. Kagaya, M. Nakano, Y. Ito, J. Ohta, H. Tada, A. Karibe, N. Minegishi, N. Suzuki, M. Yamamoto, et al. Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice Circulation, March 21, 2006; 113(11): 1442 - 1450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Imamura, B. Luo, J. Limbird, A. Vitello, M. Oka, D. D. Ivy, I. F. McMurtry, C. V. Garat, M. B. Fallon, and E. P. Carter Hypoxic pulmonary hypertension is prevented in rats with common bile duct ligation J Appl Physiol, February 1, 2005; 98(2): 739 - 747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Chattergoon, F. M. D'Souza, W. Deng, H. Chen, A. L. Hyman, P. J. Kadowitz, and J. R. Jeter Jr. Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L202 - L211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Itoh, N. Nagaya, S. Murakami, T. Fujii, T. Iwase, H. Ishibashi-Ueda, C. Yutani, M. Yamagishi, H. Kimura, and K. Kangawa C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1204 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Chicoine, E. Tzeng, R. Bryan, S. Saenz, M. L. Paffett, J. Jones, C. R. Lyons, T. C. Resta, L. D. Nelin, and B. R. Walker Intratracheal adenoviral-mediated delivery of iNOS decreases pulmonary vasoconstrictor responses in rats J Appl Physiol, November 1, 2004; 97(5): 1814 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Champion, D. Georgakopoulos, E. Takimoto, T. Isoda, Y. Wang, and D. A. Kass Modulation of In Vivo Cardiac Function by Myocyte-Specific Nitric Oxide Synthase-3 Circ. Res., March 19, 2004; 94(5): 657 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Champion, D. Georgakopoulos, S. Haldar, L. Wang, Y. Wang, and D. A. Kass Robust Adenoviral and Adeno-Associated Viral Gene Transfer to the In Vivo Murine Heart: Application to Study of Phospholamban Physiology Circulation, December 2, 2003; 108(22): 2790 - 2797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Deng, T. J. Bivalacqua, N. N. Chattergoon, A. L. Hyman, J. R. Jeter Jr., and P. J. Kadowitz Adenoviral gene transfer of eNOS: high-level expression in ex vivo expanded marrow stromal cells Am J Physiol Cell Physiol, November 1, 2003; 285(5): C1322 - C1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. D'Souza, R. L. Sparks, H. Chen, P. J. Kadowitz, and J. R. Jeter Jr. Mechanism of eNOS gene transfer inhibition of vascular smooth muscle cell proliferation Am J Physiol Cell Physiol, January 1, 2003; 284(1): C191 - C199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujita, R. J. Mason, C. Cool, J. M. Shannon, N. Hara, and K. A. Fagan Pulmonary hypertension in TNF-alpha -overexpressing mice is associated with decreased VEGF gene expression J Appl Physiol, December 1, 2002; 93(6): 2162 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Champion, T. J. Bivalacqua, S. S. Greenberg, T. D. Giles, A. L. Hyman, and P. J. Kadowitz Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice PNAS, October 1, 2002; 99(20): 13248 - 13253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Karamsetty and J. R. Klinger NO: More Than Just a Vasodilator in Lung Transplantation Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 1 - 5. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ozaki, S. Kawashima, T. Yamashita, Y. Ohashi, Y. Rikitake, N. Inoue, K.-I. Hirata, Y. Hayashi, H. Itoh, and M. Yokoyama Reduced Hypoxic Pulmonary Vascular Remodeling by Nitric Oxide From the Endothelium Hypertension, February 1, 2001; 37(2): 322 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Gelband, M. J. Katovich, and M. K. Raizada Current Perspectives on the Use of Gene Therapy for Hypertension Circ. Res., December 8, 2000; 87(12): 1118 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Budts, P. Pokreisz, Z. Nong, N. Van Pelt, H. Gillijns, R. Gerard, R. Lyons, D. Collen, K. D. Bloch, and S. Janssens Aerosol Gene Transfer With Inducible Nitric Oxide Synthase Reduces Hypoxic Pulmonary Hypertension and Pulmonary Vascular Remodeling in Rats Circulation, December 5, 2000; 102(23): 2880 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Archer and S. Rich Primary Pulmonary Hypertension : A Vascular Biology and Translational Research "Work in Progress" Circulation, November 28, 2000; 102(22): 2781 - 2791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Itano, W. Zhang, J. H. Ritter, T. J. McCarthy, T. Mohanakumar, and G. A. Patterson Adenovirus-mediated gene transfer of human interleukin 10 ameliorates reperfusion injury of rat lung isografts J. Thorac. Cardiovasc. Surg., November 1, 2000; 120(5): 947 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nagaya, C. Yokoyama, S. Kyotani, M. Shimonishi, R. Morishita, M. Uematsu, T. Nishikimi, N. Nakanishi, T. Ogihara, M. Yamagishi, et al. Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats Circulation, October 17, 2000; 102(16): 2005 - 2010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Channon, H. Qian, and S. E. George Nitric Oxide Synthase in Atherosclerosis and Vascular Injury : Insights From Experimental Gene Therapy Arterioscler Thromb Vasc Biol, August 1, 2000; 20(8): 1873 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. C. Champion, T. J. Bivalacqua, K. Toyoda, D. D. Heistad, A. L. Hyman, and P. J. Kadowitz In Vivo Gene Transfer of Prepro-Calcitonin Gene-Related Peptide to the Lung Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension in the Mouse Circulation, February 29, 2000; 101(8): 923 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Suda, B. N. Mora, F. D’Ovidio, J. A. Cooper, M. Hiratsuka, W. Zhang, T. Mohanakumar, and G. A. Patterson IN VIVO ADENOVIRUS-MEDIATED ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE TRANSFER AMELIORATES LUNG ALLOGRAFT ISCHEMIA-REPERFUSION INJURY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 297 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Faraci and C. D. Sigmund Vascular Biology in Genetically Altered Mice : Smaller Vessels, Bigger Insight Circ. Res., December 3, 1999; 85(12): 1214 - 1225. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
|
|
|
|
|
|
H. C. Champion, T. J. Bivalacqua, A. L. Hyman, L. J. Ignarro, W. J. G. Hellstrom, and P. J. Kadowitz Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat PNAS, September 28, 1999; 96(20): 11648 - 11652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Finkel Thinking Globally, Acting Locally : The Promise of Cardiovascular Gene Therapy Circ. Res., June 25, 1999; 84(12): 1471 - 1472. [Full Text] [PDF]
|
|