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      Cardiovascular Protective Effects of Synthetic Isoflavone Derivatives in Apolipoprotein E-Deficient Mice

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          Abstract

          Dietary flavonoids are thought to protect against cardiovascular disease. We have studied the effects of bioactive isoflavone metabolites on hyperlipidemia, endothelial dysfunction and the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE⁰) mice fed a Western high-fat diet. Supplementation with dihydrodaidzein (DiD), dehydroequol (DeE) (both 25 mg kg<sup>–1</sup>· day<sup>–1</sup>) and their combination (D/D; 12.5 mg kg<sup>–1</sup>·day<sup>–1</sup> for each) for 24 weeks reduced plasma high-density lipoprotein (HDL) and non-HDL cholesterol. D/D also reduced the triglyceride level. In the abdominal aorta of apoE⁰ mice, these compounds significantly increased endothelial nitric oxide (NO)-mediated vasorelaxations induced by acetylcholine, but had a minor effect on relaxations induced by the NO donor S-nitroso- N-acetylpenicillamine. Isoflavone treatment for 24 weeks had no effect on the total area of atherosclerotic plaques in the whole aorta, but DeE reduced the plaque thickness in the aortic arch by 29%, although this did not reach statistical significance. The endothelial dysfunction in apoE⁰ mice is associated with hyperlipidemia and increased vascular oxidative stress measured as increased superoxide production. Both isoflavones have superoxide-scavenging activities in vitro. We suggest that chronic supplementation with bioactive isoflavone metabolites may protect endothelial NO function in apoE⁰ mice, through both lipid-lowering and antioxidant actions.

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          Most cited references 9

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          Validation of lucigenin as a chemiluminescent probe to monitor vascular superoxide as well as basal vascular nitric oxide production.

          Lucigenin has been widely used as a chemiluminescent substrate to monitor vascular superoxide (O*-2) formation. The validity of lucigenin for detection of O*-2 has been questioned because O*-2 is generated by lucigenin itself. It has been shown that the concentration of lucigenin is a critical parameter affecting the validity of this assay. In the present studies we evaluated a reduced concentration of lucigenin (5 microM) as a tool to quantify O*-2 production in vascular tissue. Lucigenin-induced effects on endothelial function were assessed by isometric tension recording of isolated aortic rings suspended in organ baths. The effects of lucigenin on O*-2 production were studied using spin trapping and electron spin resonance spectroscopy. Lucigenin at 250 microM but not at 5 microM caused a significant attenuation of endothelium-dependent relaxations to acetylcholine, which was prevented by pretreatment with superoxide dismutase. Spin-trapping studies revealed that lucigenin at 250 microM increased vascular O*-2 production several fold while 5 microM lucigenin did not stimulate O*-2 production. Inhibition of NO synthase by NG-momomethyl-l-arginine as well as the removal of the endothelium almost doubled lucigenin-derived chemiluminescence (LDCL), indicating that basal production of endothelium-derived NO depresses the baseline chemiluminescence signal. Thus, lucigenin at a concentration of 5 microM seems to be a sensitive and valid probe for assessing O*-2 in vascular tissue. It can also be used as an indirect probe to estimate basal vascular NO release. Copyright 1999 Academic Press.
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            Lucigenin (bis-N-methylacridinium) as a mediator of superoxide anion production.

            Lucigenin (bis-N-methylacridinium) (Luc2+) has frequently been used for the luminescent detection of O2-. In fact, the pathway leading to this luminescence requires univalent reduction of Luc2+ to LucH.+ followed by formation of an unstable dioxetane by reaction of LucH.+ with O2-. It is now shown that LucH.+ rapidly autooxidizes and so produces O2-. Luc2+ can thus mediate O2- production in systems, such as glucose plus glucose oxidase, in which there is ordinarily no O2- production. Luc2+ luminescence can thus be used as the basis for assaying superoxide dismutase activity but should not be used for measuring, or even detecting, O2-.
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              Endothelial dysfunction induced by oxidized low-density lipoproteins in isolated mouse aorta: a comparison with apolipoprotein-E deficient mice.

              We characterized the acute effects of oxidized low-density lipoproteins (oxidized-LDL) on vascular reactivity in isolated aorta from wild-type C57BL/6J mice, and compared these with the chronic alterations in vascular function observed in apolipoprotein-E gene knockout [ApoE(-/-)] mice fed a high-fat diet, which results in hyperlipidemia and atherosclerosis. In the abdominal (but not thoracic) aorta, oxidized-LDL (100 microg/ml) reduced relaxations induced by acetylcholine (10(-9) M-10(-5) M), which are mediated entirely by nitric oxide (NO). The relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) M-10(-4) M), the cyclic GMP analogue 8-bromo cyclic GMP (100 microM) and the nonspecific vasodilator papaverine (100 microM) were not changed by oxidized-LDL. Native LDL had no effect on vasorelaxations. The attenuation of endothelium-dependent relaxations caused by oxidized-LDL mimicked the endothelial dysfunction found in ApoE(-/-) mice. These results are consistent with the suggestion that oxidized-LDL has an important role in the pathogenesis of endothelial NO dysfunction associated with hyperlipidemia and atherosclerosis in these mice.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2003
                June 2003
                08 August 2003
                : 40
                : 3
                : 276-284
                Affiliations
                aHoward Florey Institute, The University of Melbourne, Melbourne, Vic., Australia; bVascular Research Group, Department of Surgery, Otago Medical School, Dunedin, New Zealand; cNovogen Ltd., North Ryde, Sydney, Australia
                Article
                71891 J Vasc Res 2003;40:276–284
                10.1159/000071891
                12902640
                © 2003 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 6, Tables: 3, References: 38, Pages: 9
                Categories
                Research Paper

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