Published online before print October 16, 2006, doi: 10.1161/01.HYP.0000247304.56192.ce
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(Hypertension. 2006;48:1026.)
© 2006 American Heart Association, Inc.
Editorial Commentaries |
CuZn Superoxide Dismutase Deficiency
Culprit of Accelerated Vascular Aging Process
From the Departments of Pharmacology and Neurology, Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing, Mich.
Correspondence to Alex F. Chen, Department of Pharmacology and Toxicology, B403 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail chenal{at}msu.edu
Impairment of endothelium-dependent responses is an early landmark of endothelial dysfunction in blood vessels with aging and/or cardiovascular diseases.1 A critical manifestation of endothelial dysfunction is the reduced bioavailability of NO, a key vascular protective molecule and an independent predictor of cardiovascular events.2 Hence, stimuli decreasing vascular NO bioavailability manifest impaired endothelium-dependent relaxation.
Aging is associated with marked changes in the cardiovascular system, especially at the level of the vascular wall.3 Both structural and functional changes can take place at the level of the endothelium, vascular smooth muscle cell (VSMC), and the extracellular matrix of blood vessels. Endothelial thickening and altered endothelium-dependent responses have been reported in aged animals. Clinical studies have also shown that endothelium-dependent relaxation of both conduit and resistance vessels declines progressively with age. In contrast, endothelium-independent relaxation to sodium nitroprusside is unaffected by aging, suggesting that the impaired relaxation with age is primarily because of the dysfunctional endothelium, rather than VSMC contraction.3
Although the mechanisms underlying the aging-induced endothelial dysfunction are complex and incompletely understood, oxidative stress is a key contributor.4 Exposure of endothelial cells to increased levels of reactive oxygen species (ROS) during the aging process makes them a prime target for oxidative stress. As the first and initiating oxygen free radical in the ROS chain, superoxide (O2–) consumption of NO is one of the most important mechanisms of endothelial dysfunction.5 Vascular cells possess multifaceted protective mechanisms against the toxic effects of ROS.4–6 Among them, the 3 superoxide dismutase (SOD) isoforms, the cytosolic copper zinc SOD (CuZnSOD, SOD-1), mitochondrial manganese SOD (MnSOD, SOD-2), and extracellular SOD (EC-SOD, SOD-3), have evolved as the key enzymatic defense system for converting O2– to hydrogen peroxide (H2O2) and molecular oxygen (O2).7 The importance of SOD on endothelial function is highlighted by studies of SOD-deficient mice that manifest profound endothelial dysfunction (Table). These different isoforms, characterized by their prosthetic metal ion and cellular localization, play distinctive roles. MnSOD knockout mice exhibit neonatal lethality,8 because the vast majority of cellular ROS (estimated at 
90%) emanate from the mitochondria.9 EC-SOD, the only extracellular isoform, is a copper/zinc-containing enzyme mainly secreted by VSMCs and binds to the endothelial surface via its heparin-binding domain in the extracellular matrix.7 MnSOD and EC-SOD play pivotal roles in the regulation of the oxidant status in the mitochondria and vascular interstitium, respectively.7 Consistent with this notion, recent studies have shown that gene transfer of MnSOD or EC-SOD significantly suppresses elevated vascular O2– levels in hypertension and diabetes, respectively.10–12 The CuZn-SOD, also a copper/zinc-containing dimer SOD, is the predominant form of SOD in blood vessels, because it accounts for 50% to 80% of total SOD activity.7 The normal activity of CuZnSOD is necessary to limit increases in superoxide, allowing release of NO from endothelium and normal endothelium-dependent relaxation. Deficiency in CuZnSOD results in increased levels of vascular O2– and peroxynitrite (ONOO–) and subsequently impaired endothelium-dependent relaxation in large arteries and microvessels, as well as hypertrophy of cerebral arterioles.13,14 In contrast, overexpression of CuZnSOD decreases vascular O2– in some models of cardiovascular diseases and improves endothelial function.7 However, in the context of the vascular aging process, very little is known about the precise role of CuZn-SOD.
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In the current issue of Hypertension, Didion et al15 report that total SOD activity is significantly lower in aorta of young heterozygous CuZnSOD-deficient mice (ie, CuZnSOD+/–) compared with that of age-matched wild-type mice (ie, 7 month old) and aged CuZnSOD+/– mice (ie, 22 to 24 months old), accompanied by increased O2– levels. Endothelium-dependent relaxation of the carotid artery is markedly impaired in CuZnSOD+/– but not wild-type mice with aging. This is the first time that striking vascular phenotype in aging heterozygous CuZn-SOD-deficient mice has been described, which adds new and important insights into the mechanisms underlying CuZnSOD protection of the endothelial cell from dysfunction and cell loss. In addition, tempol (an O2– scavenger) restores endothelium-dependent responses in CuZnSOD+/– mice with aging, providing strong evidence that the impaired response to acetylcholine in old CuZnSOD+/– mice is mediated by O2– in a reversible manner. These findings suggest that normal CuZnSOD expression protects endothelial function and that deficiency in a single copy of the gene accelerates endothelial dysfunction with aging.
It is also interesting to note that serotonin-induced contractile response, but not the thromboxane analog 9,11-dideoxy-11a,9a-epoxy-methanoprostoglandin-F2a (U46619), is enhanced with aging in heterozygous CuZnSOD mice. The selectively enhanced contractile response may reflect a reduction in NO bioavailability associated with CuZnSOD deficiency and aging, because it is consistent with the similarly observed response in endothelial NO synthase–deficient mice.16 However, the impact of changes in expression of CuZn-SOD in an aging vessel can be more complex than simply affecting NO bioavailability. For instance, overexpression of CuZnSOD protects VSMCs from oxidized low-density lipoprotein–induced DNA fragmentation and caspase activation, resulting in decreased oxidized low-density lipoprotein–induced apoptosis.17 These data imply that that DNA damage may be an important mediator of endothelial dysfunction. To provide further insight into the mechanism underlying the impaired endothelium-dependent response that occurs with the combination of aging and reductions in CuZnSOD, the authors then investigated the role of poly-ADP-ribose polymerase (PARP) in endothelial dysfunction in CuZnSOD+/– mice with aging. PARP, abundant in the eukaryotic nucleus, can be activated by oxidant-induced DNA injury.18 ROS, including O2–, ONOO–, and H2O2, are endogenous inducers of single-strand DNA, which is the trigger of PARP activation. When single-strand DNA breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD+ and ATP pools, which slows the rate of glycolysis and mitochondrial respiration leading to cellular dysfunction and cell death.19 The present study demonstrates that acute treatment with the competitive PARP inhibitor, PJ34, normalizes the impaired endothelium-dependent relaxation in carotid arteries of 24-month-old aging CuZnSOD+/– mice. This new observation provides a possible mechanism that the impairment of endothelium-dependent relaxation is related to endothelial depletion of reduced nicotinamide-adenine dinucleotide (an essential cofactor of NO synthase) because of PARP overactivation. It is also possible that the activated PARP in endothelial cells during aging and the subsequent energetic failure induces endothelial cell apoptosis or necrosis, which leads to the loss and dysfunction of endothelial cells (Figure).
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Similar to cardiovascular disease conditions, the ability of aging vascular cells to detoxify ROS and replace oxidatively damaged macromolecules could become inefficient.7 A loss of adaptive responses to oxidative stress with the passage of time is one of the major characteristics of aging.6 Evidence also suggests that the cellular antioxidative defense system is attenuated during the aging process.3 Augmented release of O2– and subsequent reaction with NO yielding the highly reactive oxidant ONOO– could be a key mechanism for age-associated endothelial dysfunction, which characterizes the vascular aging process. Indeed, the increased formation of ONOO– during aging could inactivate antioxidative enzymes, such as MnSOD, in the mitochondria.20 The dismutation product of O2–, H2O2, could attenuate the EC-SOD in extracellular space (Figure).21 The present study indicates that the impairment of vascular responses with aging in heterozygous CuZnSOD deficiency is because of aging but not the presence of potentially confounding disease states, such as atherosclerotic lesions, hypertension, and hyperglycemia. This suggests that normal CuZnSOD plays a critical role in protecting blood vessels in response to oxidative stress during aging. Future studies are needed to determine the possible mechanisms of loss of CuZnSOD with advanced aging.
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Acknowledgments |
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Sources of Funding
Supported by grants from the National Institutes of Health R01 GM077352 and the American Heart Association Grant-in-Aid 0655642Z.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Esper RJ, Nordaby RA, Vilarino JO, Paragano A, Cacharron JL, Machado RA. Endothelial dysfunction: a comprehensive appraisal. Cardiovasc Diabetol. 2006; 5: 4–21.[CrossRef][Medline] [Order article via Infotrieve]
2. Thomas SR, Chen K, Keaney JF Jr. Oxidative stress and endothelial nitric oxide bioactivity. Antioxid Redox Signal. 2003; 5: 181–194.[CrossRef][Medline] [Order article via Infotrieve]
3. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005; 66: 286–294.
4. Harman D. The free radical theory of aging. Antioxid Redox Signal. 2003; 5: 557–561.[CrossRef][Medline] [Order article via Infotrieve]
5. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000; 408: 239–247.[CrossRef][Medline] [Order article via Infotrieve]
6. Yu BP, Chung HY. Adaptive mechanisms to oxidative stress during aging. Mech Ageing Dev. 2006; 127: 436–443.[Medline] [Order article via Infotrieve]
7. Faraci FM, Didion SP. Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler Thromb Vasc Biol. 2004; 24: 1367–1373.
8. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995; 11: 376–381.[CrossRef][Medline] [Order article via Infotrieve]
9. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005; 120: 483–495.[CrossRef][Medline] [Order article via Infotrieve]
10. Li LX, Crockett E, Wang DH, Galligan JJ, Fink GD, Chen AF. Gene transfer of endothelial NO synthase and manganese superoxide dismutase on arterial vascular cell adhesive molecule-1 expression and superoxide production in deoxycorticosterone acetate-salt hypertension. Arterioscler Thromb Vasc Biol. 2002; 22: 249–255.
11. Li L, Chu Y, Fink GD, Engelhardt JF, Heistad DD, Chen AF. Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension. 2003; 42: 997–1003.
12. Luo JD, Wang YY, Fu WL, Wu J, Chen AF. Gene therapy of endothelial nitric oxide synthase and manganese superoxide dismutase restores delayed wound healing in type 1 diabetic mice. Circulation. 2004; 110: 2484–2493.
13. Didion SP, Ryan MJ, Didion LA, Fegan PE, Sigmund CD, Faraci FM. Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res. 2002; 91: 938–944.
14. Baumbach GL, Didion SP, Faraci FM. Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase. Stroke. 2006; 37: 1850–1855.
15. Didion SP, Kinzenbaw DA, Schrader LI, Faraci FM. Heterozygous CuZn superoxide dismutase deficiency produces a vascular phenotype with aging. Hypertension. 2006; 48: 1072–1079.
16. Lamping KG, Faraci FM. Role of sex differences and effects of endothelial NO synthase deficiency in responses of carotid arteries to serotonin. Arterioscler Thromb Vasc Biol. 2001; 21: 523–528.
17. Guo Z, Van Remmen H, Yang H, Chen X, Mele J, Vijg J, Epstein CJ, Ho YS, Richardson A. Changes in expression of antioxidant enzymes affect cell-mediated LDL oxidation and oxidized LDL-induced apoptosis in mouse aortic cells. Arterioscler Thromb Vasc Biol. 2001; 21: 1131–1138.
18. Garcia Soriano F, Virag L, Jagtap P, Szabo E, Mabley JG, Liaudet L, Marton A, Hoyt DG, Murthy KG, Salzman AL, Southan GJ, Szabo C. Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nat Med. 2001; 7: 108–113.[CrossRef][Medline] [Order article via Infotrieve]
19. Pacher P, Mabley JG, Soriano FG, Liaudet L, Komjati K, Szabo C. Endothelial dysfunction in aging animals: the role of poly (ADP-ribose) polymerase activation. Br J Pharmacol. 2002; 135: 1347–1350.[CrossRef][Medline] [Order article via Infotrieve]
20. van der Loo B, Labugger R, Skepper JN, Bachschmid M, Kilo J, Powell JM, Palacios-Callender M, Erusalimsky JD, Quaschning T, Malinski T, Gygi D, Ullrich V, Luscher TF. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000; 192: 1731–1744.
21. Fukai T, Folz RJ, Landmesser U, Harrison DG. Extracellular superoxide dismutase and cardiovascular disease. Cardiovasc Res. 2002; 55: 239–249.
Related Article:
Hypertension 2006 48: 1072-1079.
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