doi: 10.1161/01.ATV.0000258920.36436.8e
© 2007 American Heart Association, Inc.
Editorials |
Extracellular SOD Inactivation in High-Volume Hypertension
Role of Hydrogen Peroxide
From the Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago.
Correspondence to Tohru Fukai, MD, PhD, Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403MSB, Chicago, IL 60612. E-mail tfukai{at}uic.edu
Excessive reactive oxygen species (ROS), especially superoxide anion (O2•–), contribute to the pathogenesis of many cardiovascular diseases, including hypertension. The major antioxidant defense system against O2•– is superoxide dismutases (SODs). In mammals, 3 isoforms of superoxide dismutase exist: the cytoplasmic CuZnSOD (SOD1), the mitochondrial MnSOD (SOD2), and the extracellular Cu/ZnSOD (SOD3, ecSOD). The ecSOD is the major SOD in the vascular extracellular space, and synthesized by vascular smooth muscle cells and fibroblasts. It is secreted and anchored to the extracellular matrix and endothelial cell surface through binding to the heparan sulfate proteoglycan, collagen, and fibulin-5.1–3 Of note, the R213G polymorphism in the ecSOD gene, which reduces binding to endothelial surface and increases serum ecSOD levels, has been linked to an increase in cardiovascular risk.4
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Nitric oxide (NO•) produced by endothelium stimulates vasodilation of vascular smooth muscle and thus exerts antihypertensive action. Because O2•– reacts with NO• at almost diffusion-limited rates, ecSOD which scavenges O2•– in the vascular extracellular space plays an important role in regulating bioactivity of NO•.1 Indeed, gene transfer of ecSOD reduces O2•– and restores impairment of endothelium dependent relaxation, resulting in the decrease in arterial pressure in a genetic model of hypertension.5 Furthermore, ecSOD has peroxidase activity in which H2O2, the dismutation product of O2•–, can inactivate ecSOD by reacting with the copper center of ecSOD, thereby forming the Cu–OH radical and leading to enzyme inactivation.6 This effect can be prevented by scavenging the Cu–OH radical with small anionic antioxidants, such as urate or nitrite. In apolipoprotein E–/– mice, ecSOD activity is reduced, and can be restored by increasing the plasma concentration of urate (Figure).6
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In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Jung et al provide evidence that ecSOD is inactivated in the 1-kidney–1-clip (1K1C) model of low renin and high volume hypertension.7 In this model, the increase in blood pressure in ecSOD–/– mice and ecSOD+/+ mice is not significantly different, but is decreased by an administration of recombinant ecSOD. This result suggests that low renin and high volume hypertension model is dependent on insufficient amount or lack of ecSOD. Furthermore, the authors demonstrated that ecSOD protein level is markedly elevated with a slight increase in ecSOD activity in the 1K1C model, suggesting that a large amount of ecSOD protein induced by 1K1C is inactive. To test the hypothesis that ecSOD has peroxidase activity, Jung et al examined the effects of polyethylene glycol (PEG)-catalase and the hydroxyl radical scavenger uric acid on blood pressure and endothelium-dependent relaxation in ecSOD+/+ and ecSOD–/– mice with 1K1C model. They showed that either PEG-catalase or oxonic acid (which increases uric acid by inhibiting uricase) inhibits hypertension induced by 1K1C in ecSOD+/+ mice, but not in ecSOD–/– mice, which is associated with an improvement of endothelium dependent relaxation. The blood pressure lowering effect of PEG-catalase is not attributable to H2O2 formed by ecSOD, because acute infusion of PEG-catalase has no effect. Thus, these results indicate that endogenous ecSOD does not provide sufficient activity to scavenge extracellular O2•–, resulting in promoting the increase in O2•– level, which may contribute to enhancing blood pressure and impairment of endothelium dependent relaxation in high volume hypertension (Figure).
Consistent with this finding in the 1K1C model, the authors and others reported that ecSOD deficiency promotes O2•– increases and impairment of endothelium dependent relaxation in aortas from mice with the two-kidney and one-clip (2K1C) model (high renin induced hypertension) and in small mesenteric arteries from mice with chronic angiotensin II infusion, which is associated with an enhanced increase in blood pressure.8,9 By contrast, application of ecSOD fails to improve vascular function in ecSOD+/+ mice with 2K1C model, indicating that inactivation of ecSOD does not occur in aortas of SOD+/+ mice in this model.9 In another high volume hypertension model such as DOCA salt hypertension in which O2•– is increased via eNOS uncoupling, treatment of catalase impair, instead of improve, endothelium dependent relaxation.10 In an atherosclerosis model, both ecSOD and Cu/ZnSOD are inactivated, which can be rescued by increasing uric acid, a scavenger for hydroxyl radical and peroxynitrite,6 whereas ecSOD is selectively inactivated in 1K1C model.
Another important finding in this article is that administration of ecSOD has no effect on blood pressure induced by 1K1C in eNOS–/– mice or in mice with LNNA treatment, suggesting that the blood pressure–lowering effect of ecSOD is dependent on NO• derived from eNOS. Given that NO• stimulates ecSOD expression,11,12 a feed-forward mechanism may exist whereby ecSOD induced by NO• decreases blood pressure through increasing NO bioactivity. Although a role of peroxynitrite in inactivation of SODs remains unclear, H2O2 seems to play a more important role in 1K1C model because PEG-catalase lowers blood pressure to a similar level as ecSOD treatment (Figure). In the current study, the authors demonstrated that peroxynitrite inactivates ecSOD and Cu/ ZnSOD without affecting MnSOD. By contrast, others showed that peroxynitrite inactivates MnSOD, but it has no or milder effect on Cu/ZnSOD in vitro.13,14 Furthermore, tyrosine nitration and inactivation of MnSOD are observed in chronic rejection of human renal allografts,15 suggesting that inactivation of MnSOD by peroxynitrite may play a role in their model. Understanding a role of peroxynitrite in regulating activity of Cu/ZnSOD and ecSOD in oxidative stress–dependent cardiovascular diseases including vascular injury16 and atherosclerosis6 requires further investigation.
It has been controversial whether serum levels of uric acid are an independent risk factor for cardiovascular disease in humans. Several previous studies including an analysis from the Framingham Heart Study showed a "J-shaped" relationship of serum uric acid with coronary heart disease and cardiovascular disease mortality.17,18 Interestingly, Jung et al in this article demonstrated that increasing uric acid by treatment with oxonic acid improves endothelium dependent vasorelaxation and lowered blood pressure in 1K1C hypertensive ecSOD+/+ mice. Together with previous findings in atherosclerosis,6 these results may explain why lowering serum uric acid levels can be associated with higher risk of cardiovascular disease.17,18
The information presented by Jung et al and previous studies strongly supports a critical role of "extracellular" superoxide in hypertension.8,9,19 It is important to understand how vascular cells release O2•– extracellularly, and how ecSOD activity and expression are regulated. There are many unanswered questions. In another high volume hypertension model, DOCA salt hypertension, why does treatment of catalase impair, instead of improve, endothelium dependent relaxation10? Why does the inactivation of ecSOD fail to occur in ecSOD+/+ mice with 2K1C model (high renin-induced hypertension)9? What is the mechanism by which ecSOD expression is increased in aortas from 1K1C model? Does inactivation of ecSOD occur at other organs, such as kidney in 1K1C model? Why are both ecSOD and Cu/ZnSOD inactivated in the atherosclerosis model whereas ecSOD only is inactivated in the 1K1C model? Addressing these questions will be essential to our understanding the critical role of ecSOD in the tenuous balance between O2•– and NO• and will provide increasing insight into ecSOD as a potential therapeutic target for treatment of oxidative stress–dependent cardiovascular diseases such as hypertension.
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Acknowledgments |
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Sources of Funding
This research was supported by NIH R01 HL70187 and AHA Grant-In-Aid 0455242B.
Disclosures
None.
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References |
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Arterioscler. Thromb. Vasc. Biol. 2007 27: 470-477.
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