Advertisement

Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis

      Abstract

      Objective

      Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells.

      Methods and results

      Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H2O2. Edaravone treatment (10 mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24 h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H2O2-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10 mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18 ± 0.01 to 0.09 ± 0.01 mm2, P < 0.001) and descending aorta (5.09 ± 0.86 to 1.75 ± 0.41 mm2, P < 0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment.

      Conclusions

      These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ross R.
        Atherosclerosis—an inflammatory disease.
        N Engl J Med. 1999; 340: 115-126
        • Griendling K.K.
        • Sorescu D.
        • Lassegue B.
        • Ushio-Fukai M.
        Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology.
        Arterioscler Thromb Vasc Biol. 2000; 20: 2175-2183
        • Zalba G.
        • San Jose G.
        • Moreno M.U.
        • et al.
        Oxidative stress in arterial hypertension: role of NAD(P)H oxidase.
        Hypertension. 2001; 38: 1395-1399
        • Sorescu D.
        • Weiss D.
        • Lassegue B.
        • et al.
        Superoxide production and expression of nox family proteins in human atherosclerosis.
        Circulation. 2002; 105: 1429-1435
        • Spiekermann S.
        • Landmesser U.
        • Dikalov S.
        • et al.
        Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation.
        Circulation. 2003; 107: 1383-1389
        • Rey F.E.
        • Li X.C.
        • Carretero O.A.
        • Garvin J.L.
        • Pagano P.J.
        Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox).
        Circulation. 2002; 106: 2497-2502
        • Barry-Lane P.A.
        • Patterson C.
        • van der Merwe M.
        • et al.
        p47phox is required for atherosclerotic lesion progression in ApoE(−/−) mice.
        J Clin Invest. 2001; 108: 1513-1522
        • Keaney Jr., J.F.
        • Gaziano J.M.
        • Xu A.
        • et al.
        Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.
        Proc Natl Acad Sci (USA). 1993; 90: 11880-11884
        • Keaney Jr., J.F.
        • Xu A.
        • Cunningham D.
        • Jackson T.
        • Frei B.
        • Vita J.A.
        Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.
        J Clin Invest. 1995; 95: 2520-2529
        • Lamb D.J.
        • Reeves G.L.
        • Taylor A.
        • Ferns G.A.
        Dietary copper supplementation reduces atherosclerosis in the cholesterol-fed rabbit.
        Atherosclerosis. 1999; 146: 33-43
        • Pratico D.
        • Tangirala R.K.
        • Rader D.J.
        • Rokach J.
        • FitzGerald GA
        Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice.
        Nat Med. 1998; 4: 1189-1192
        • Li Z.
        • Iwai M.
        • Wu L.
        • et al.
        Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis.
        Hypertension. 2004; 44: 758-763
        • Fennell J.P.
        • Brosnan M.J.
        • Frater A.J.
        • et al.
        Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension.
        Gene Ther. 2002; 9: 110-117
        • Kirk E.A.
        • Dinauer M.C.
        • Rosen H.
        • Chait A.
        • Heinecke J.W.
        • LeBoeuf R.C.
        Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice.
        Arterioscler Thromb Vasc Biol. 2000; 20: 1529-1535
        • Hsich E.
        • Segal B.H.
        • Pagano P.J.
        • et al.
        Vascular effects following homozygous disruption of p47(phox): an essential component of NADPH oxidase.
        Circulation. 2000; 101: 1234-1236
        • Fang J.C.
        • Kinlay S.
        • Beltrame J.
        • et al.
        Effect of Vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial.
        Lancet. 2002; 359: 1108-1113
        • Engler M.M.
        • Engler M.B.
        • Malloy M.J.
        • et al.
        Antioxidant Vitamins C and E improve endothelial function in children with hyperlipidemia: endothelial assessment of risk from lipids in youth (EARLY) trial.
        Circulation. 2003; 108: 1059-1063
        • Lonn E.
        • Bosch J.
        • Yusuf S.
        • et al.
        Effects of long-term Vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial.
        JAMA. 2005; 293: 1338-1347
        • Lee I.M.
        • Cook N.R.
        • Gaziano J.M.
        • et al.
        Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
        JAMA. 2005; 294: 56-65
        • Study-Group E.
        Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters.
        Cerebrovasc Dis. 2003; 15: 222-229
        • Abe S.
        • Kirima K.
        • Tsuchiya K.
        • et al.
        The reaction rate of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186)) with hydroxyl radical.
        Chem Pharm Bull (Tokyo). 2004; 52: 186-191
        • Watanabe T.
        • Yuki S.
        • Egawa M.
        • Nishi H.
        Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions.
        J Pharmacol Exp Ther. 1994; 268: 1597-1604
        • Sudoh N.
        • Toba K.
        • Akishita M.
        • et al.
        Estrogen prevents oxidative stress-induced endothelial cell apoptosis in rats.
        Circulation. 2001; 103: 724-729
        • Akishita M.
        • Nagai K.
        • Xi H.
        • et al.
        Renin–angiotensin system modulates oxidative stress-induced endothelial cell apoptosis in rats.
        Hypertension. 2005; 45: 1188-1193
        • Paigen B.
        • Morrow A.
        • Holmes P.A.
        • Mitchell D.
        • Williams R.A.
        Quantitative assessment of atherosclerotic lesions in mice.
        Atherosclerosis. 1987; 68: 231-240
        • Miller Jr., F.J.
        • Gutterman D.D.
        • Rios C.D.
        • Heistad D.D.
        • Davidson B.L.
        Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis.
        Circ Res. 1998; 82: 1298-1305
        • Landmesser U.
        • Dikalov S.
        • Price S.R.
        • et al.
        Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.
        J Clin Invest. 2003; 111: 1201-1209
        • Francia P.
        • Delli Gatti C.
        • Bachschmid M.
        • et al.
        Deletion of p66shc gene protects against age-related endothelial dysfunction.
        Circulation. 2004; 110: 2889-2895
        • Carter W.O.
        • Narayanan P.K.
        • Robinson J.P.
        Intracellular hydrogen peroxide and superoxide anion detection in endothelial cells.
        J Leuk Biol. 1994; 55: 253-258
        • Xi H.
        • Shin W.S.
        • Suzuki J.
        • et al.
        Dystrophin disruption might be related to myocardial cell apoptosis caused by isoproterenol.
        J Cardiovasc Pharmacol. 2000; 36: S25-S29
        • Esterbauer H.
        • Schaur R.J.
        • Zollner H.
        Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.
        Free Radic Biol Med. 1991; 11: 81-128
        • Meigs J.B.
        • Hu F.B.
        • Rifai N.
        • Manson J.E.
        Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus.
        JAMA. 2004; 291: 1978-1986
        • Uchida K.
        • Toyokuni S.
        • Nishikawa K.
        • et al.
        Michael addition-type 4-hydroxy-2-nonenal adducts in modified low-density lipoproteins: markers for atherosclerosis.
        Biochemistry. 1994; 33: 12487-12494
        • Usatyuk P.V.
        • Natarajan V.
        Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells.
        J Biol Chem. 2004; 279: 11789-11797
        • Jiang F.
        • Guo Y.
        • Salvemini D.
        • Dusting G.J.
        Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein (E)-deficient mice.
        Br J Pharmacol. 2003; 139: 1127-1134
        • O’Donnell V.B.
        • Chumley P.H.
        • Hogg N.
        • Bloodsworth A.
        • Darley-Usmar V.M.
        • Freeman B.A.
        Nitric oxide inhibition of lipid peroxidation: kinetics of reaction with lipid peroxyl radicals and comparison with alpha-tocopherol.
        Biochemistry. 1997; 36: 15216-15223
        • White C.R.
        • Brock T.A.
        • Chang L.Y.
        • et al.
        Superoxide and peroxynitrite in atherosclerosis.
        Proc Natl Acad Sci USA. 1994; 91: 1044-1048
        • Zheng H.
        • Dimayuga C.
        • Hudaihed A.
        • Katz S.D.
        Effect of dexrazoxane on homocysteine-induced endothelial dysfunction in normal subjects.
        Arterioscler Thromb Vasc Biol. 2002; 22: E15-E18
        • Terentis A.C.
        • Thomas S.R.
        • Burr J.A.
        • Liebler D.C.
        • Stocker R.
        Vitamin E oxidation in human atherosclerotic lesions.
        Circ Res. 2002; 90: 333-339
        • Marui N.
        • Offermann M.K.
        • Swerlick R.
        • et al.
        Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.
        J Clin Invest. 1993; 92: 1866-1874
        • Park S.H.
        • Park J.H.
        • Kang J.S.
        • Kang Y.H.
        Involvement of transcription factors in plasma HDL protection against TNF-alpha-induced vascular cell adhesion molecule-1 expression.
        Int J Biochem Cell Biol. 2003; 35: 168-182
        • Tsujimoto I.
        • Hikoso S.
        • Yamaguchi O.
        • et al.
        The antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy.
        Hypertension. 2005; 45: 921-926
        • Amemiya S.
        • Kamiya T.
        • Nito C.
        • et al.
        Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats.
        Eur J Pharmacol. 2005; 516: 125-130
        • Doi K.
        • Suzuki Y.
        • Nakao A.
        • Fujita T.
        • Noiri E.
        Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney.
        Kidney Int. 2004; 65: 1714-1723
        • Tsujita K.
        • Shimomura H.
        • Kawano H.
        • et al.
        Effects of edaravone on reperfusion injury in patients with acute myocardial infarction.
        Am J Cardiol. 2004; 94: 481-484
        • Yoshida H.
        • Sasaki K.
        • Namiki Y.
        • Sato N.
        • Edaravone T.N.
        a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase.
        Atherosclerosis. 2005; 179: 97-102
        • Zhang X.H.
        • Matsuda N.
        • Jesmin S.
        • et al.
        Normalization by edaravone, a free radical scavenger, of irradiation-reduced endothelial nitric oxide synthase expression.
        Eur J Pharmacol. 2003; 476: 131-137
        • Cipollone F.
        • Fazia M.
        • Iezzi A.
        • et al.
        High preprocedural non-HDL cholesterol is associated with enhanced oxidative stress and monocyte activation after coronary angioplasty: possible implications in restenosis.
        Heart. 2003; 89: 773-779