Circulation Research. 2003
Published online before print February 27, 2003, doi: 10.1161/01.RES.0000063424.28903.BB
Published online before print February 27, 2003, doi: 10.1161/01.RES.0000063424.28903.BB
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on January 24, 2002
Revised on February 4, 2003
Accepted on February 12, 2003
Increased Superoxide Generation Is Associated With Pulmonary Hypertension in Fetal Lambs. A Role for NADPH Oxidase
Lisa A. Brennan ;
From the Departments of Pediatrics (L.A.B., R.H.S., S.W., E.M.-G., E.A.R., S.M.B.) and Molecular Pharmacology (S.M.B.), Northwestern University, Chicago, Ill, and the Department of Physiology (J.A.R.), State University of Buffalo, New York.
* To whom correspondence should be addressed. E-mail: steveblack{at}northwestern.edu.
Ligation of the ductus arteriosus in utero produces pulmonary hypertension and vascular remodeling in fetal and newborn lambs. However, the mechanisms producing these vascular changes are not well defined. Because reactive oxygen species (ROS) have been implicated as mediators of smooth muscle cell proliferation, we hypothesized that increased formation of ROS may be involved in the pathophysiology of pulmonary hypertension after in utero ductal ligation. Using ethidium fluorescence, we demonstrated an increase in superoxide levels after 9 days of ductal ligation compared with control lungs (P<0.05) that was localized to the adventitia and smooth muscle cells of hypertensive vessels. SOD-1 and SOD-2 protein levels and activities in lung, vein, and artery of hypertensive lambs were unchanged relative to controls after 2 days of ductal ligation. However, after 9 days, superoxide dismutase (SOD) activity was significantly decreased in arteries from ligated lambs without associated changes in SOD protein expression (P<0.05). Examination of NADPH oxidase expression as a potential source of the superoxide production indicated that the levels of p67phox, a subunit of the NADPH oxidase complex, were significantly increased in the pulmonary arteries, but not veins, from the ligated lung as early as 2 days (P<0.05). Functional analyses demonstrated that reducing superoxide levels significantly increased the NO-mediated relaxation of pulmonary arteries isolated after 9 days, but not 2 days, of ductal ligation (P<0.05). These results suggest that increased NADPH oxidase expression may increase levels of superoxide in persistent pulmonary hypertension of the newborn lung tissue, and that increased superoxide blunts vascular relaxations to exogenous NO while stimulating smooth muscle cell growth.
Key words: reactive oxygen species • vascular remodeling • smooth muscle
This article has been cited by other articles:
 |
|
 |
|
  K. N. Farrow, S. Lakshminrusimha, W. J. Reda, S. Wedgwood, L. Czech, S. F. Gugino, J. M. Davis, J. A. Russell, and R. H. Steinhorn Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L979 - L987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Lopez-Lopez, J. Moral-Sanz, G. Frazziano, M. J. Gomez-Villalobos, J. Flores-Hernandez, E. Monjaraz, A. Cogolludo, and F. Perez-Vizcaino Diabetes induces pulmonary artery endothelial dysfunction by NADPH oxidase induction Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L727 - L732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Fike, J. C. Slaughter, M. R. Kaplowitz, Y. Zhang, and J. L. Aschner Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L881 - L888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kumar, X. Sun, S. Wedgwood, and S. M. Black Hydrogen peroxide decreases endothelial nitric oxide synthase promoter activity through the inhibition of AP-1 activity Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L370 - L377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. N. Farrow, B. S. Groh, P. T. Schumacker, S. Lakshminrusimha, L. Czech, S. F. Gugino, J. A. Russell, and R. H. Steinhorn Hyperoxia Increases Phosphodiesterase 5 Expression and Activity in Ovine Fetal Pulmonary Artery Smooth Muscle Cells Circ. Res., February 1, 2008; 102(2): 226 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-X. Shi, Y. Chen, Y.-Z. Zhu, G.-Y. Huang, P. K. Moore, S.-H. Huang, T. Yao, and Y.-C. Zhu Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2093 - H2100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Sanders and J. R. Hoidal The NOX on Pulmonary Hypertension Circ. Res., August 3, 2007; 101(3): 224 - 226. [Full Text] [PDF]
|
|
|
|
|
|
G. G. Konduri, I. Bakhutashvili, A. Eis, and K. Pritchard Jr. Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1812 - H1820. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bedard and K.-H. Krause The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology Physiol Rev, January 1, 2007; 87(1): 245 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H Steinhorn and K. N Farrow Pulmonary Hypertension in the Neonate NeoReviews, January 1, 2007; 8(1): e14 - e21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lakshminrusimha, J. A. Russell, S. Wedgwood, S. F. Gugino, J. A. Kazzaz, J. M. Davis, and R. H. Steinhorn Superoxide Dismutase Improves Oxygenation and Reduces Oxidation in Neonatal Pulmonary Hypertension Am. J. Respir. Crit. Care Med., December 15, 2006; 174(12): 1370 - 1377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Grobe, S. M. Wells, E. Benavidez, P. Oishi, A. Azakie, J. R. Fineman, and S. M. Black Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1069 - L1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sturrock, B. Cahill, K. Norman, T. P. Huecksteadt, K. Hill, K. Sanders, S. V. Karwande, J. C. Stringham, D. A. Bull, M. Gleich, et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L661 - L673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Mata-Greenwood, C. Jenkins, K. N. Farrow, G. G. Konduri, J. A. Russell, S. Lakshminrusimha, S. M. Black, and R. H. Steinhorn eNOS function is developmentally regulated: uncoupling of eNOS occurs postnatally Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L232 - L241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cai A new mechanism for flow-mediated vasoprotection? Focus on "Lung endothelial cell proliferation with decreased shear stress is mediated by reactive oxygen species" Am J Physiol Cell Physiol, January 1, 2006; 290(1): C35 - C36. [Full Text] [PDF]
|
|
|
|
|
|
J. Q. Liu, I. N. Zelko, E. M. Erbynn, J. S. K. Sham, and R. J. Folz Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox) Am J Physiol Lung Cell Mol Physiol, January 1, 2006; 290(1): L2 - L10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-F. Lam, T. E. Peterson, A. J. Croatt, K. A. Nath, and Z. S. Katusic Functional adaptation and remodeling of pulmonary artery in flow-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2334 - H2341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wedgwood, R. H. Steinhorn, M. Bunderson, J. Wilham, S. Lakshminrusimha, L. A. Brennan, and S. M. Black Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn Am J Physiol Lung Cell Mol Physiol, October 1, 2005; 289(4): L660 - L666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Fike, Y. Zhang, and M. R. Kaplowitz Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets J Appl Physiol, August 1, 2005; 99(2): 670 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Mata-Greenwood, A. Grobe, S. Kumar, Y. Noskina, and S. M. Black Cyclic stretch increases VEGF expression in pulmonary arterial smooth muscle cells via TGF-{beta}1 and reactive oxygen species: a requirement for NAD(P)H oxidase Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L288 - L289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Khoo, L. Zhao, N. J. Alp, J. K. Bendall, T. Nicoli, K. Rockett, M. R. Wilkins, and K. M. Channon Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension Circulation, April 26, 2005; 111(16): 2126 - 2133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wedgwood and S. M. Black Endothelin-1 decreases endothelial NOS expression and activity through ETA receptor-mediated generation of hydrogen peroxide Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L480 - L487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Patil, M. Bunderson, J. Wilham, and S. M. Black Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1314 - L1322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Jernigan, B. R. Walker, and T. C. Resta Endothelium-derived reactive oxygen species and endothelin-1 attenuate NO-dependent pulmonary vasodilation following chronic hypoxia Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L801 - L808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. L. Jernigan, T. C. Resta, and B. R. Walker Contribution of oxygen radicals to altered NO-dependent pulmonary vasodilation in acute and chronic hypoxia Am J Physiol Lung Cell Mol Physiol, May 1, 2004; 286(5): L947 - L955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Minuz, P. Patrignani, S. Gaino, F. Seta, M. L. Capone, S. Tacconelli, M. Degan, G. Faccini, A. Fornasiero, G. Talamini, et al. Determinants of Platelet Activation in Human Essential Hypertension Hypertension, January 1, 2004; 43(1): 64 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Wedgwood and S. M. Black Induction of apoptosis in fetal pulmonary arterial smooth muscle cells by a combined superoxide dismutase/catalase mimetic Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L305 - L312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Bland, C. Y. Ling, K. H. Albertine, D. P. Carlton, A. J. MacRitchie, R. W. Day, and M. J. Dahl Pulmonary vascular dysfunction in preterm lambs with chronic lung disease Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L76 - L85. [Abstract] [Full Text] [PDF]
|
|