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 (10–8M) 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 µM) 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.

Keywords:
Endothelium, Oxidative stress, HMG-CoA reductase inhibitors
1.
Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, River C: Urocortin, a mammalian neuropeptide related to fish urotensin 1 and to corticotrophin-releasing factor. Nature 1995;378:287–292.
2.
Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Suzuki H, Nagura H, Yoshimi T: Urocortin expression in human pituitary gland and pituitary adenoma. J Clin Endocrinol Metab 1997;82:3842–3850.
3.
Takahashi K, Totsune K, Sone M, Murakami O, Satoh F, Arihara Z, Sasano H, Iino K, Mouri T: Regional distribution of urocortin-like immunoreactivity and expression of urocortin mRNA in the human brain. Peptide 1998;19:643–647.
4.
Petraglia F, Florio P, Gallo R, Simoncini T, Saviozzi M, Di Blasio AM, Vaughan J, Vale W: Human placenta and fetal membranes express human urocortin mRNA and peptide. J Clin Endocrinol Metab 1996;81:3807–3810.
5.
Chatzaki E, Charalampopolos I, Leontidis C, Mouzas IA, Tzardi M, Tsatsanis C, Margioris AN, Gravanis A: Urocortin in human gastric mucosa: relationship to inflammatory activity. J Clin Endocrinol Metab 2003;88:478–483.
6.
Kohno M, Kawahito Y, Tsubouchi Y, Hashiramoto A, Yamada R, Inoue K, Kusaka Y, Kubo T, Elenkov IJ, Chrousos G, Kondo M, Sano H: Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity. J Clin Endocrinol Metab 2001;86:4344–4352.
7.
Bamberger CM, Wald M, Bamberger AM, Ergun S, Beri FU, Schulte HM: Human lymphocytes produce urocortin, but not corticotropin-releasing hormone. J Clin Endocrinol Metab 1998;83:708–711.
8.
Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M: Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab 2004;89:965–970.
9.
Kimura Y, Takahashi K, Totsune K, Muramatsu Y, Kaneko C, Darnel AD, Suzuki T, Ebina M, Nukiwa T, Sasano H: Expression of urocortin and corticotrophin-releasing factor receptor subtypes in the human heart. J Clin Endocrinol Metab 2002;87:340–346.
10.
Rademaker MT, Charles CJ, Espiner E, Fisher S, Frampton CM, Kirkpatrick CMJ, Lainchbury J, Nicholls G, Richards M, Vale W: Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep. J Am Coll Cardiol 2002;40:1495–1505.
11.
Huag Y, Chan F, Lau CW, Tsang SY, Chen ZY, He GW, Yao X: Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent relaxation by urocortin in the rat coronary artery. Cardiovascular Research 2003;57:824–833.
12.
Parkes DG, Vaughan J, Rivier J, Vale W, May CN: Cardiac inotropic actions of urocortin in conscious sheep. Am J Physiol 1997;272:H2115–H2122.
13.
Scarabelli TM, Pasini E, Stephanou A, Comini L, Curello S, Raddino R, Ferrari R, Knight R, Latchman D: Urocortin promotes hemodynamic and bioenergic recovery and improves cell survival in the isolated rat heart exposed to ischemia/reperfusion. J Am Coll Cardiol 2002;40:155–161.
14.
Gordon JM, Gregory JD, Owen LW, Dusting GJ, Woodman OL: Cardioprotective action of CRF peptide urocortin against stimulated ischemia in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 2003;284:H330–H336.
15.
Lawrence KM, Chanalaris A, Scarabelli T, Hubank M, Pasini E, Townsend PA, Comini L, Ferrari R, Tinker A, Stephanou A, Kight R, Litchman D: KATP channel gene expression is induced by urocortin and mediates its cardioprotective effect. Circulation 2002;106:1556–1562.
16.
Schulman D, Latchman DS, Yellon DM: Urocortin protects the heart from reperfusion injury via upregulation of p42/p44 MAPK signaling pathway. Am J Physiol Heart Circ Physiol 2002;283:H1481–H1488.
17.
Brar BK, Jonassen AK, Stephanou A, Santilli G, Railson J, Knight RA, Yellon DM, Latchman DS: Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem 2000;275:8508–8514.
18.
Kishimoto T, Pearse RV, Lin CR, Rosenfeld MG: A sauvagine/corticotrophin-releasing factor receptor expressed in heart and skeletal muscle. Proc Natl Acad Sci USA 1995;92:1108–1112.
19.
Wiley KE, Davenport AP: CRF2 receptors are highly expressed in the human cardiovascular system and their cognate ligands urocortins 2 and 3 are potent vasodilators. Br J Pharmacol 2004;143:508–514.
20.
Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH, Murray SE, Hill JK, Pantely GA, Hohimer AR, Hatton DC, Phillips TJ, Finn DA, Low MJ, Rittenberg MB, Stenzel P, Stenzel-Poore MP: Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 2000;24:403–409.
21.
Florio P, Arcuri F, Ciarmela P, Runci Y, Romagnoli R, Cintorino M, Di Blasio AM, Petraglia F: Identification of urocortin mRNA and peptide in the human endometrium. J Endocrinol 2002;173:R9–R14.
22.
Simoncini T, Apa R, Reis FM, Miceli F, Stomati M, Driul L, Lanzone A, Genazzani AR, Petraglia F: Human umbilical vein endothelial cells: a new source and potential target for corticotropin-releasing factor. J Clin Endocrinol Metab 1999;84:2802–2806.
23.
Node K, Fujita M, Kitakaze M, Hori M, Liao JK: Short-term statin therapy improves cardiac function and symptom in patients with idiopathic dilated cardiomyopathy. Circulation 2003;108:839–843.
24.
Agnello D, Bertini R, Sacco S, Meazza C, Villa P, Ghezzi P: Corticosteroid-independent inhibition of tumor necrosis factor production by the neuropeptide urocortin. Am J Physiol 1998;275:E757–E762.
25.
Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E: Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230–235.
26.
Ridker PM, Rifai N, Lowenthal SP: Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001;103:1191–1193.
27.
Rikitake Y, Kawashima S, Takeshita S, Yamashita T, Azumi H, Yasuhara M, Nishi H, Inoue N, Yokoyama M: Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 2001;154:87–96.
28.
Treasure CB, Klein L, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi S, Cedarholm J, Alexander W: Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481–487.
29.
Takamoto M, Liao JK: Pleiotropic effects of 3-hydoxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Tromb Vasc Biol 2001;21:1712–1719.
30.
Liao JK: Beyond lipid lowering: the role of statins in vascular protection. Int J Cardiol 2002;86:5–18.
31.
Kobayashi S, Inoue N, Ohashi Y, Terashima M, Matsui K, Mori T, Fujita H, Awano K, Kobayashi K, Azumi H, Ejiri J, Hirata K, Kawashima S, Hayashi Y, Yokozaki H, Itoh H, Yokoyama M: Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein. Arterioscler Thromb Vasc Biol 2003;23:1398–1404.
© 2006 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.