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      Endothelial Urocortin Has Potent Antioxidative Properties and Is Upregulated by Inflammatory Cytokines and Pitavastatin

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          Abstract

          Background: Urocortin, a neuropeptide discovered in the midbrain, is a member of the corticotropin-releasing factor family and is expressed in heart tissues. Urocortin exerts potent cardioprotective effects under various pathological conditions including ischemia/reperfusion. However, the regulation and function of vascular urocortin are unknown. Methods and Results: Immunohistochemistry showed definitive expression of urocortin in endothelial cells of coronary large arteries and microvessels from autopsied hearts. RT-PCR confirmed the expression of urocortin in human umbilical vein endothelial cells (HUVECs). Urocortin (10<sup>–8</sup> M) potently suppressed the generation of angiotensin II-induced reactive oxygen species (ROS) in HUVECs. Tumor necrosis factor-α and interferon-γ increased the urocortin mRNA levels and its release from HUVECs. Incubation with pitavastatin (0.1–3.0 µ M) significantly increased the urocortin mRNA levels and its release from HUVECs. Furthermore, treatment with pitavastatin (2 mg/day) for 4 weeks increased the serum urocortin level from 11.0 ± 6.5 to 16.4 ± 7.3 ng/ml in healthy volunteers. Conclusion: Endothelial urocortin was upregulated by inflammatory cytokines and pitavastatin and suppressed ROS production in endothelial cells. Treatment with pitavastatin increased the serum urocortin level in human subjects. Thus, endothelial urocortin might protect cardiomyocytes in inflammatory lesions. Urocortin might partly explain the mechanisms of various pleiotropic effects of statins.

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          Most cited references 18

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          Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.

          The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation. Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.
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            Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor.

            Corticotropin-releasing factor (CRF), a peptide first isolated from mammalian brain, is critical in the regulation of the pituitary-adrenal axis, and in complementary stress-related endocrine, autonomic and behavioural responses. Fish urotensin I and amphibian sauvagine were considered to be homologues of CRF until peptides even more closely related to CRF were identified in these same vertebrate classes. We have characterized another mammalian member of the CRF family and have localized its urotensin-like immunoreactivity to, and cloned related complementary DNAs from, a discrete rat midbrain region. The deduced protein encodes a peptide that we name urocortin, which is related to urotensin (63% sequence identity) and CRF (45% sequence identity). Synthetic urocortin evokes secretion of adrenocorticotropic hormone (ACTH) both in vitro and in vivo and binds and activates transfected type-1 CRF receptors, the subtype expressed by pituitary corticotropes. The coincidence of urotensin-like immunoreactivity with type-2 CRF receptors in brain, and our observation that urocortin is more potent than CRF at binding and activating type-2 CRF receptors, as well as at inducing c-Fos (an index of cellular activation) in regions enriched in type-2 CRF receptors, indicate that this new peptide could be an endogenous ligand for type-2 CRF receptors.
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              Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.

              The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.
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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
                2006
                February 2006
                16 February 2006
                : 43
                : 2
                : 131-138
                Affiliations
                aDivision of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, and bDivision of Surgical Pathology, Department of Biological Informatics, Kobe University Graduate School of Medicine, Kobe, Japan
                Article
                90132 J Vasc Res 2006;43:131–138
                10.1159/000090132
                16340217
                © 2006 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: 5, Tables: 1, References: 31, Pages: 8
                Categories
                Research Paper

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