© 1999 American Heart Association, Inc.
Editorials |
Dual Role of Reactive Oxygen Species in Vascular Growth
From the Division of Cardiology, Emory University, Atlanta, Ga.
Correspondence to Kathy K. Griendling, PhD, Emory University, Division of Cardiology, 1639 Pierce Dr, 319 WMB, Atlanta, GA 30322. E-mail kgriend{at}emory.edu
Key Words: vascular smooth muscle • hydrogen peroxide • apoptosis • superoxide • proliferation
 |
Introduction |
|---|
 Top Introduction References |
|---|
In the last decade, it has become clear that virtually all mammalian cells produce reactive oxygen species. It was generally believed that these were by-products of cellular respiration and metabolism, and that they exerted toxic effects, including DNA damage and lipid oxidation. Recent evidence has demonstrated that this concept is incorrect, and that reactive oxygen species are produced in a controlled fashion and likely have critical signaling functions. Likewise, antioxidant defenses play a crucial role in modulating the ambient steady-state levels of reactive oxygen species. Biological or pharmacological manipulation of endogenous antioxidants can have a profound effect on cellular function.
Emerging evidence suggests that hydrogen peroxide (H2O2) plays a particularly important role in signal transduction. H2O2 is uncharged and is freely diffusible within and between cells. Compared with other reactive oxygen species, it is also quite stable. A major source of H2O2 is a membrane-bound NADH/NADPH oxidase, the activity of which is regulated by hormones, growth factors, and physical forces. The primary product of this enzyme system is superoxide (O2·-), which is rapidly dismutated to H2O2 by the superoxide dismutases. Removal of H2O2 is regulated by two important enzymes, catalase and glutathione peroxidase. Reaction products of H2O2, including lipid hydroperoxides, are also biologically active.
Given the fact that the molecule is diffusible and stable and that its production and removal are highly regulated, H2O2 is an obvious candidate as a second messenger. Indeed, many studies have demonstrated that H2O2 mediates intracellular responses to extracellular stimuli. Early work showed that both tyrosine kinases and tyrosine phosphatases were targets of exogenous H2O2, and more recently several groups have demonstrated that agonist-induced activation of these enzymes is redox sensitive. Strong evidence for an involvement of H2O2 in ERK1/2 and p38 MAPK activation by growth factors and angiotensin II has been obtained by treating cells with exogenous catalase or by stably overexpressing catalase.1 2 H2O2 has also been shown to mediate epidermal growth factor–induced phosphorylation of its receptor and phospholipase C,3 platelet-derived growth factor (PDGF) stimulation of STATs,4 activation of Akt by angiotensin II,5 and tyrosine phosphorylation of protein kinase C.6 Activation of ras by reactive oxygen species is also potentially quite important.7 Recently, it has been shown that catalase, after reacting with H2O2, can activate guanylate cyclase. This seems to occur via a unique mechanism that is quite different from the heme-mediated activation of guanylate cyclase by nitric oxide.8
In this issue of Circulation Research, Brown et al9 present evidence that overexpression of human catalase has dual effects on vascular smooth muscle cells. Using an adenoviral construct to express up to a 50- to 100-fold excess of catalase, they demonstrate that smooth muscle cells overexpressing catalase have decreased rates of DNA synthesis and cell proliferation and higher rates of apoptosis. Catalase-overexpressing cells also show an induction of COX-2 protein, which may modulate cell growth by increasing the formation of growth-inhibitory prostaglandin, PGE2. This possibility is supported by the observation that a COX-2 inhibitor reversed the reduction in cell number consequent to catalase overexpression.
The study of Brown et al9 is in keeping with previous reports that reactive oxygen species mediate the response of smooth muscle cells to growth-promoting agents. Sundaresen et al2 showed that not only did PDGF increase intracellular H2O2 but also that incubation of vascular smooth muscle cells with catalase prevented DNA synthesis in response to PDGF. Similarly, stable transfecton of rat aortic smooth muscle cells with human catalase blocked angiotensin II–induced H2O2 production and hypertrophy.10 The concept that reactive oxygen species are growth promoting is further supported by the observations of Tsai et al,11 who reported that treatment of vascular smooth muscle cells with the antioxidants N-acetyl-cysteine or pyrrolidine dithiocarbamate dose dependently reduced cell viability and enhanced apoptosis. These findings agree well with observations of Brown et al9 that overexpression of catalase, another antioxidant, also increased apoptosis.
Not all studies agree that oxidant stress is growth promoting, and in fact, others have shown that H2O2 actually may enhance apoptosis.12 Fiorani et al13 found that although H2O2 initially increases DNA synthesis, this increase is followed by cell death. Similarly, exposure of vascular smooth muscle cells to glucose/glucose oxidase (which generates H2O2) induces apoptosis via the formation of hydroxyl radicals.14 The resolution of this apparent paradox is likely related to the levels and identity of the reactive oxygen species and antioxidants under consideration. Thus, although a certain level of oxidant stress appears to be growth promoting, more severe stress may lead to cell death. Similarly, treatment with excess antioxidants, either pharmacologically or by overexpression of endogenous enzymes, may reduce the level of reactive oxygen species below that necessary for survival, triggering entry into the apoptotic pathway. Additional experimentation will be necessary to reconcile these disparate observations.
The information presented by Brown et al,9 together with other recent studies, strongly supports a role of H2O2 as an important signaling molecule in vascular smooth muscle. Interestingly, it seems that H2O2 shares some similarities to nitric oxide in this regard. Both nitric oxide and H2O2 are reactive oxygen species that are freely diffusible between cells. Both nitric oxide and H2O2 have different effects depending on their concentration. It has now become clear that H2O2 has specific cellular targets, as does nitric oxide, and the biological effects of both of these reactive oxygen species seem critical to normal vascular function. Future studies of the endogenous reactive oxygen species, including H2O2, are essential in allowing an understanding of how these small molecules affect vascular cells under normal and pathophysiological conditions.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Ushio-Fukai M, Alexander RW, Akers M, Griendling KK. p38 MAP kinase is a critical component of the redox-sensitive signaling pathways by angiotensin II: role in vascular smooth muscle cell hypertrophy. J Biol Chem. 1998;273:15022–15029.
2.
Sundaresan M, Zu-Xi Y, Ferrans VJ, Irani K, Finkel T.
Requirement for generation of
H2O2 for
platelet-derived growth factor signal transduction.
Science. 1995;270:296–299.
3.
Bae YS, Kang SW, Seo MS, Baines IC, Takle E, Chock PB,
Rhee SG. Epidermal growth factor (EGF)-induced generation of hydrogen
peroxide. Role in EGF receptor-mediated tyrosine
phosphorylation. J Biol
Chem. 1997;272:217–221.
4.
Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of
the JAK-STAT pathway by reactive oxygen species. Am J
Physiol. 1998;275:C1640–C1652.
5.
Ushio-Fukai M, Alexander RW, Akers M, Yin Q, Fujio Y,
Walsh K, Griendling KK. Reactive oxygen species mediate the activation
of Akt/Protein kinase B by angiotensin II in vascular
smooth muscle cells. J Biol Chem. 1999;274:22699–22704.
6.
Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y,
Kikkawa U, Nishizuka Y. Activation of protein kinase C by tyrosine
phosphorylation in response to
H2O2. Proc Natl Acad
Sci U S A. 1997;94:11233–11237.
7.
Lander HM, Ogiste JS, Teng KK, Novogrodsky A. p21ras
as a common signaling target of reactive free radicals and cellular
redox stress. J Biol Chem. 1995;270:21195–21198.
8.
Mohazzab-H KM, Agarwal R, Wolin MS. Influence of
glutathione peroxidase on coronary artery responses to
alterations in PO2 and
H2O2. Am J
Physiol. 1999;276:H235–H241.
9.
Brown MR, Miller FJ Jr, Li WG, Ellingson AN, Mozena
JD, Chatterjee P, Engelhardt JF, Zwacha RM, Oberley LW, Fang X, Spector
AA, Weintraub NL. Overexpression of human catalase inhibits
proliferation and promotes apoptosis in vascular smooth muscle
cells. Circ Res. 1999;85:524–533.
10.
Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A,
Harrison DG, Taylor WR, Griendling KK. Novel role of NADH/NADPH
oxidase-derived hydrogen peroxide in angiotensin II-induced
hypertrophy of rat vascular smooth muscle cells.
Hypertension. 1998;32:488–495.
11.
Tsai MH, Yu CL, Stacey DW. A cytoplasmic protein
inhibits the GTPase activity of H-Ras in a phospholipid-dependent
manner. Science. 1990;250:982–985.
12.
Li P, Dietz R, von Harsdorf R. Differential effect of
hydrogen peroxide and superoxide anion on apoptosis and
proliferation of vascular smooth muscle cells. Circulation. 1997;96:3602–3609.
13. Fiorani M, Cantoni O, Tasinato A, Boscoboinik D, Azzi A. Hydrogen peroxide- and fetal bovine serum-induced DNA synthesis in vascular smooth muscle cells: positive and negative regulation by protein kinase C isoforms. Biochim Biophys Acta. 1995;1269:98–104.[Medline] [Order article via Infotrieve]
14. Li PF, Dietz R, von Harsdorf R. Reactive oxygen species induce apoptosis of vascular smooth muscle. FEBS Lett. 1997;404:249–252.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. J. Haurani and P. J. Pagano Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res, September 1, 2007; 75(4): 679 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Chan, S. R. Datla, R. Dilley, H. Hickey, G. R. Drummond, and G. J. Dusting Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits Cardiovasc Res, September 1, 2007; 75(4): 710 - 718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Sung, A. Yee, S. G. Eskin, and L. V. McIntire Cyclic strain and motion control produce opposite oxidative responses in two human endothelial cell types Am J Physiol Cell Physiol, July 1, 2007; 293(1): C87 - C94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Thengchaisri, R. Shipley, Y. Ren, J. Parker, and L. Kuo Exercise Training Restores Coronary Arteriolar Dilation to NOS Activation Distal to Coronary Artery Occlusion: Role of Hydrogen Peroxide Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 791 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schmelter, B. Ateghang, S. Helmig, M. Wartenberg, and H. Sauer Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation FASEB J, June 1, 2006; 20(8): 1182 - 1184. [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]
|
|
|
|
 |
|
 K. Matsushita, C. N. Morrell, R. J.A. Mason, M. Yamakuchi, F. A. Khanday, K. Irani, and C. J. Lowenstein Hydrogen peroxide regulation of endothelial exocytosis by inhibition of N-ethylmaleimide sensitive factor J. Cell Biol., July 4, 2005; 170(1): 73 - 79. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cai NAD(P)H Oxidase-Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease Circ. Res., April 29, 2005; 96(8): 818 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Noronha, J.-M. Li, S. B. Wheatcroft, A. M. Shah, and M. T. Kearney Inducible Nitric Oxide Synthase Has Divergent Effects on Vascular and Metabolic Function in Obesity Diabetes, April 1, 2005; 54(4): 1082 - 1089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Barton Ageing as a determinant of renal and vascular disease: role of endothelial factors Nephrol. Dial. Transplant., March 1, 2005; 20(3): 485 - 490. [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Mazak, A. Fiebeler, D. N. Muller, J.-K. Park, E. Shagdarsuren, C. Lindschau, R. Dechend, C. Viedt, B. Pilz, H. Haller, et al. Aldosterone Potentiates Angiotensin II-Induced Signaling in Vascular Smooth Muscle Cells Circulation, June 8, 2004; 109(22): 2792 - 2800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Haendeler, J. Hoffmann, R. P. Brandes, A. M. Zeiher, and S. Dimmeler Hydrogen Peroxide Triggers Nuclear Export of Telomerase Reverse Transcriptase via Src Kinase Family-Dependent Phosphorylation of Tyrosine 707 Mol. Cell. Biol., July 1, 2003; 23(13): 4598 - 4610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Mingone, S. A. Gupte, S. Quan, N. G. Abraham, and M. S. Wolin Influence of Heme and Heme Oxygenase-1 Transfection of Pulmonary Microvascular Endothelium on Oxidant Generation and cGMP Experimental Biology and Medicine, May 1, 2003; 228(5): 535 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, J. J. Galligan, G. D. Fink, and A. F. Chen Vasopressin Induces Vascular Superoxide Via Endothelin-1 in Mineralocorticoid Hypertension Hypertension, March 1, 2003; 41(3): 663 - 668. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Schulze, G. W. De Keulenaer, J. Yoshioka, K. A. Kassik, and R. T. Lee Vitamin D3-Upregulated Protein-1 (VDUP-1) Regulates Redox-Dependent Vascular Smooth Muscle Cell Proliferation Through Interaction With Thioredoxin Circ. Res., October 18, 2002; 91(8): 689 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Ballinger, C. Patterson, C. A. Knight-Lozano, D. L. Burow, C. A. Conklin, Z. Hu, J. Reuf, C. Horaist, R. Lebovitz, G. C. Hunter, et al. Mitochondrial Integrity and Function in Atherogenesis Circulation, July 30, 2002; 106(5): 544 - 549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. NICKENIG, S. BAUDLER, C. MULLER, C. WERNER, N. WERNER, H. WELZEL, K. STREHLOW, and M. BOHM Redox-sensitive vascular smooth muscle cell proliferation is mediated by GKLF and Id3 in vitro and in vivo FASEB J, July 1, 2002; 16(9): 1077 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Locher, R. P. Brandes, W. Vetter, and M. Barton Native LDL Induces Proliferation of Human Vascular Smooth Muscle Cells via Redox-Mediated Activation of ERK 1/2 Mitogen-Activated Protein Kinases Hypertension, February 1, 2002; 39(2): 645 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]
|
|
|
|
 |
|
 S. V. Kalivendi, S. Kotamraju, H. Zhao, J. Joseph, and B. Kalyanaraman Doxorubicin-induced Apoptosis Is Associated with Increased Transcription of Endothelial Nitric-oxide Synthase. EFFECT OF ANTIAPOPTOTIC ANTIOXIDANTS AND CALCIUM J. Biol. Chem., December 7, 2001; 276(50): 47266 - 47276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. E.J. West, H. Qian, T. J. Guzik, E. Black, S. Cai, S. E. George, and K. M. Channon Nitric Oxide Synthase (nNOS) Gene Transfer Modifies Venous Bypass Graft Remodeling: Effects on Vascular Smooth Muscle Cell Differentiation and Superoxide Production Circulation, September 25, 2001; 104(13): 1526 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Wayne Alexander Cytokine Receptor CX3CR-1 and Fractalkine: New Factors in the Atherosclerosis Drama? Circ. Res., August 31, 2001; 89(5): 376 - 377. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Niebauer, P. S Tsao, P. S Lin, R. E Pratt, and J. P Cooke Cholesterol-induced upregulation of angiotensin II and its effects on monocyte-endothelial interaction and superoxide production Vascular Medicine, August 1, 2001; 6(3): 133 - 138. [Abstract] [PDF]
|
|
|
|
 |
|
 M. P. Stojiljkovic, D. Zhang, H. F. Lopes, C. G. Lee, T. L. Goodfriend, and B. M. Egan Hemodynamic effects of lipids in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1674 - R1679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, R. Niculescu, D. Wang, S. Patel, K. L. Davenpeck, and A. Zalewski Increased NAD(P)H Oxidase and Reactive Oxygen Species in Coronary Arteries After Balloon Injury Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 739 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Czubryt, J. A. Austria, and G. N. Pierce Hydrogen Peroxide Inhibition of Nuclear Protein Import Is Mediated by the Mitogen-Activated Protein Kinase, Erk2 J. Cell Biol., January 10, 2000; 148(1): 7 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lopez-Ongil, V. Senchak, M. Saura, C. Zaragoza, M. Ames, B. Ballermann, M. Rodriguez-Puyol, D. Rodriguez-Puyol, and C. J. Lowenstein Superoxide Regulation of Endothelin-converting Enzyme J. Biol. Chem., August 18, 2000; 275(34): 26423 - 26427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Heeneman, J. Haendeler, Y. Saito, M. Ishida, and B. C. Berk Angiotensin II Induces Transactivation of Two Different Populations of the Platelet-derived Growth Factor beta Receptor. KEY ROLE FOR THE p66 ADAPTOR PROTEIN Shc J. Biol. Chem., May 19, 2000; 275(21): 15926 - 15932. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||