Published online before print July 3, 2003, doi: 10.1161/01.STR.0000081984.07414.EF
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2003;34:1956.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Elevated Uric Acid and Ischemic Stroke: Accumulating Evidence That It Is Injurious and Not Neuroprotective
Section of Nephrology, Baylor College of Medicine, Houston, Texas
Hyperuricemia was first associated with hypertension and cardiovascular disease in 1879.1 Since that time, many have attributed this association to a simple clustering of hyperuricemia with well-established cardiovascular risk factors, and an elevated serum uric acid level by itself has generally been regarded as insignificant or incidental. A recent reanalysis of the Framingham study concluded that hyperuricemia was not an independent risk factor for cardiovascular events after controlling for these other associated factors.2 Nevertheless, other studies have found an elevated serum uric acid level to be an independent risk factor for cardiovascular and renal disease (reviewed elsewhere3). In particular, several studies have reported that hyperuricemia is an independent predictor of stroke in diabetic subjects,4 individuals with isolated systolic hypertension,5,6 and the general population.7 A new study reported in this issue of Stroke8 examining 2498 subjects admitted with acute stroke found that the admission serum uric acid also independently predicted worse outcome and a higher rate of repeated stroke or other cardiovascular event. Others have also reported that a higher uric acid level in patients with acute stroke is associated with poorer outcome.9 These studies suggest that uric acid may be a true risk factor for stroke and for a poor outcome after stroke.
Experimental evidence could provide a mechanism to explain how uric acid may have a pathogenetic role in stroke. Hypertension remains the most common cause of stroke, and there is increasing evidence that an elevation in uric acid may cause primary hypertension. Elevated serum uric acid is an independent predictor of hypertension10 and is present in the vast majority of adolescents with new-onset, untreated primary hypertension.11 Experimentally induced hyperuricemia also causes hypertension in rats by a renal mechanism linked to inhibition of nitric oxide, activation of the renin-angiotensin system, and development of renal arteriolosclerosis.12 Once the renal arteriolosclerosis develops, the kidney drives the hypertension, and lowering uric acid is no longer protective.13 Prolonged hyperuricemia in rats also causes progressive renal injury via a crystalline-independent mechanism12 and can accelerate established renal disease14; the mechanism is mediated by an elevation in glomerular pressure and renal vasoconstriction.15 Finally, uric acid stimulates synthesis of monocyte chemoattractant protein-1 by rat vascular smooth muscle cells,16 which is known to have a key role in stimulating macrophage infiltration in atherosclerotic vessels.17 It is of interest that uric acid is strongly associated with carotid18,19 and coronary20 atherosclerosis, especially in women.
There is also a potential pathogenetic mechanism to explain why an elevated serum uric acid at the time of stroke may be injurious. Recent evidence suggests that acute ischemic stroke results in generation of local oxidants that augment local injury and increase infarct size.21 Acute stroke is associated with a rapid decrease in serum antioxidants22,23 that recover slowly over the subsequent week.24 Individuals with lower plasma antioxidants at the time of acute stroke have a poorer outcome.25 Uric acid is often considered an antioxidant and has been shown to scavenge hydrogen peroxide and hydroxyl radicals, to block nitrotyrosine formation from peroxynitrite, and to preserve extracellular superoxide dismutase.26,27 Several studies suggest that its antioxidant properties may have a beneficial role in multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease.28 One might therefore expect that having elevated uric acid during an acute stroke would be beneficial. However, only 1 small study has reported that elevated uric acid is associated with good outcome after an ischemic stroke,29 whereas 2 other studies, including the large series reported in the current issue, found the opposite.8,9 One explanation is that uric acid, being an aqueous antioxidant, can become a pro-oxidant under certain circumstances, particularly if other antioxidants such as ascorbate are low.30 Thus, the fall in ascorbate (vitamin C) levels with acute stroke could predispose the serum uric acid to take on pro-oxidant properties. Consistent with this hypothesis is the observation that in acute stroke, those with high uric acid and low ascorbate levels have the worst outcome.24
Further studies are needed to prove whether uric acid has a pathogenetic role in hypertension, vascular disease, atherosclerosis, and stroke. It will also be important to determine whether lowering uric acid levels reduces the frequency of stroke. One wonders if the increased benefit of losartan over atenolol in the Losartan Intervention For Endpoint Reduction in Hypertension Study may relate in part to the uricosuric effect of losartan and the consequent lower uric acid levels.31 It is also important to assess whether elevated uric acid levels, especially when coupled with low ascorbate levels, may function more as a pro-oxidant than as an antioxidant. It is of interest that there is often a J-shaped curve when one compares uric acid levels with cardiovascular events,3 because this might suggest that low uric acid levels may increase mortality as a result of inadequate antioxidant levels and high levels of uric acid may function more as a pro-oxidant to increase the predisposition for the development of hypertension and vascular disease. It may also explain why studies in rats suggest that administering uric acid is beneficial in ischemic stroke32; in this case, uric acid may be functioning more as an antioxidant because uric acid levels are lower in rats as a result of the presence of the enzyme uricase. In the meantime, studies such as the one in the current issue8 provide strong evidence that an elevated uric acid is injurious rather than protective in subjects with acute stroke.
 |
Acknowledgments |
|---|
This work is supported by NIH grants DK-52121, HL-68607, and 1P50-DK064233–01. Dr Kanellis is supported by a CJ Martin Fellowship from the Australian National Health and Medical Research Council.
|
References |
|---|
 Top References |
|---|
1. Mahomed FA. On chronic Bright’s disease, and its essential symptoms. Lancet. 1879; 1: 399–401.
2. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk of cardiovascular disease and mortality: the Framingham Heart Study. Ann Intern Med. 1999; 31: 7–13.
3. Johnson RJ, Kang D-H, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M. Is there a pathogenetic role for uric acid in hypertension, cardiovascular, and renal disease? Hypertension. 2003; 41: 1183–1190.
4. Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non–insulin-dependent diabetes mellitus. Stroke. 1998; 29: 635–639.
5. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB. Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program. J Hypertens. 2000; 18: 1149–1154.[CrossRef][Medline] [Order article via Infotrieve]
6. Wang J-G, Staessen JA, Fagard RH, Birkenhäger WH, Gong L, Liu L. Prognostic significance of serum creatinine and uric acid in older Chinese patients with isolated systolic hypertension. Hypertension. 2001; 37: 1069–1074.
7. Mazza A, Pessina AC, Pavei A, Scarpa R, Tikhonoff V, Casiglia E. Predictors of stroke mortality in elderly people from the general population. Eur J Epidemiol. 2001; 17: 1097–1104.[CrossRef][Medline] [Order article via Infotrieve]
8. Weir CJ, Muir SW, Walters MR, Lees KR. Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke. 2003; 34: 1951–1957.
9. Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, di Ioirio A, Senin U, Mecocci P. Antioxidant profile and early outcome in stroke patients. Stroke. 2000; 31: 2295–2300.
10. Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Galasso R, Mancini M, Trevisan M. Serum uric acid and hypertension: the Olivetti Heart Study. J Hum Hypertens. 1994; 8: 677–681.[Medline] [Order article via Infotrieve]
11. Feig DI, Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. In press.
12. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001; 38: 1101–1106.
13. Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, Johnson RJ. Uric acid, hominoid evolution and the pathogenesis salt-sensitivity. Hypertension. 2002; 40: 355–360.
14. Kang D, Nakagawa T, Feng L, Truong L, Harris RC, Johnson RJ. A role for uric acid in renal progression. J Am Soc Nephrol. 2002; 13: 2888–2897.
15. Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol. 2002; 283: F1105–F1110.
16. Kanellis J, Watanabe S, Li JH, Kang D-H, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003; 41: 1287–1293.
17. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2: 275–281.[CrossRef][Medline] [Order article via Infotrieve]
18. Crouse JR, Toole JF, McKinney WM, Dignan MB, Howard G, Kahl FR, McMahan MR, Harpold GH. Risk factors fro extracranial carotid artery atherosclerosis. Stroke. 1987; 18: 990–996.
19. Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis. 2000; 148: 131–139.[CrossRef][Medline] [Order article via Infotrieve]
20. Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary artery disease. Am J Cardiol. 2001; 87: 1411–1414.[CrossRef][Medline] [Order article via Infotrieve]
21. Love S. Oxidative stress in brain ischemia. Brain Pathol. 1999; 9: 119–131.[Medline] [Order article via Infotrieve]
22. Gariballa SE, Hutchin TP, Sinclair AJ. Antioxidant capacity after acute ischaemic stroke. Q J Med. 2002; 95: 685–690.
23. Spranger M, Krempien S, Schwab S, Donneberg S, Hacke W. Superoxide dismutase activity in serum of patients with acute cerebral ischemic injury. Stroke. 1997; 28: 2425–2428.
24. Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, di Iorio A, Senin U, Mecocci P. Antioxidant profile and early outcome in stroke patients. Stroke. 2000; 31: 2295–2300.
25. Leinonen JS, Ahonen J-P, Lönrot K, Jehkonen M, Dastidar P, Molnár G, Alho H. Low plasma anti-oxidant activity is associated with high lesion volume and neurological impairment in stroke. Stroke. 2000; 31: 33–39.
26. Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, Pryor WA. Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000; 376: 333–337.[CrossRef][Medline] [Order article via Infotrieve]
27. Hink HU, Santanam N, Dikalov S, McCann L, Nguyen AD, Parthasarathy S, Harrison DG, Fukai T. Peroxidase properties of extracellular superoxide dismutase. Role of uric acid in modulating in vivo activity. Arterioscler Thromb Vasc Biol. 2002; 22: 1402–1408.
28. Hooper DC, Scott GS, Zborek A, Mkheeva T, Kean RB, Koprowski H, Spitsin SV. Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J. 2000; 14: 691–698.
29. Chamorro Á, Obach V, Cervera Á, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002; 33: 1048–1052.
30. Abuja PM. Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein. FEBS Lett. 1999; 446: 305–308.[CrossRef][Medline] [Order article via Infotrieve]
31. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]
32. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res. 1998; 53: 613–625.[CrossRef][Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  P. H. Proctor Uric Acid and Neuroprotection Stroke, August 1, 2008; 39(8): e126 - e126. [Full Text] [PDF]
|
|
|
|
 |
|
 Fuhua Peng, Bin Zhang, Xiufeng Zhong, Jin Li, Guihong Xu, Xueqiang Hu, Wei Qiu, and Zhong Pei Serum uric acid levels of patients with multiple sclerosis and other neurological diseases Multiple Sclerosis, March 1, 2008; 14(2): 188 - 196. [Abstract] [PDF]
|
|
|
|
|
|
A. Chamorro, A. M. Planas, C. J. Weir, S. W. Muir, M. R. Walters, and K. R. Lees Yin and Yang of Uric Acid in Patients With Stroke * Response Stroke, January 1, 2004; 35 (1): e11 - e12. [Full Text] [PDF]
|
|
|
|
 |
|
 What Role Does Urate Play in Stroke? Journal Watch Neurology, November 7, 2003; 2003(1107): 4 - 4. [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||