Background/Aims: Plasminogen activator inhibitor-1 (PAI-1), thrombospondin-1 (THBS1) and thrombomodulin (TM) are involved in atherothrombosis. Vitamin D receptor agonists (VDRAs) provide survival/cardiovascular benefits for chronic kidney disease patients. Methods: The effects of VDRAs on regulating PAI-1, THBS1 and TM in human aortic smooth muscle cells (SMC) and endothelial cells (EC) were studied. Results: In SMC, paricalcitol and calcitriol downregulated the expression of PAI-1 mRNA and protein in a dose-dependent manner (EC50 = 0.7 and 4.4 nM, respectively). Both drugs also downregulated THBS1 mRNA and protein (EC50 = 1.6 and 3.9 nM, respectively). In contrast, paricalcitol and calcitriol upregulated TM mRNA and protein (EC50 = 28.9 and 25.5 nM, respectively). EC did not express VDR, and VDRAs failed to induce CYP24A1, a VDR target gene. The effect of paricalcitol on THBS1 in SMC was blocked by cycloheximide, while its effect on TM and CYP24A1 was not affected, suggesting that the regulation of THBS1 by VDR may be mediated through intermediate factors, but that TM is likely a direct target of VDR. Conclusion: VDR may play a role in atherothrombosis via regulation of PAI-1, THBS1 and TM.

1.
Andress DL: Vitamin D treatment in chronic kidney disease. Semin Dial 2005;18:315–321.
2.
Brown AJ, Dusso AS, Slatopolsky E: Vitamin D analogues for secondary hyperparathyroidism. Nephrol Dial Transplant 2002;17:10–19.
3.
Carlberg C, Quack M, Herdick M, Bury Y, Polly P, Toell A: Central role of VDR conformations for understanding selective actions of vitamin D(3) analogues. Steroids 2001;66:213–221.
4.
Zebrack JS, Anderson JL, Beddhu S, Horne BD, Bair TL, Cheung A, Muhlestein JB: Do associations with C-reactive protein and extent of coronary artery disease account for the increased cardiovascular risk of renal insufficiency? J Am Coll Cardiol 2003;42:57–63.
5.
Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, Salem DN, Levey AS, Sarnak MJ: Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol 2004;15:1307–1315.
6.
Martin KJ, Gonzalez EA: Vitamin D analogs: actions and role in the treatment of secondary hyperparathyroidism. Semin Nephrol 2004;24:456–459.
7.
Nakai S, Shinzato T, Nagura Y, Masakane I, Kitaoka T, Shinoda T, Yamazaki C, Sakai R, Ohmori H, Morita O, Iseki K, Kikuchi K, Kubo K, Suzuki K, Tabei K, Fushimi K, Miwa N, Wada A, Yanai M, Akiba T: An overview of regular dialysis treatment in Japan (as of 31 December 2001). Ther Apher Dial 2004;8:3–32.
8.
Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003;349:446–456.
9.
Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, Thadhani R: Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005;16:1115–1125.
10.
Shoji T, Shinohara K, Kimoto E, Emoto M, Tahara H, Koyama H, Inaba M, Fukumoto S, Ishimura E, Miki T, Tabata T, Nishizawa Y: Lower risk for cardiovascular mortality in oral 1α-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant 2004;19:179–184.
11.
Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP, Kilpatrick RD, Shinaberger CS, McAllister CJ, Budoff MJ, Salusky IB, Kopple JD: Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006;70:771–780.
12.
Young EW, Albert JM, Akiba T, Greenwood R, Kimata N, W. LN, Piera L, Saran R: Vitamin D therapy and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol 2005;16:TH-PO0735.
13.
Raggi P: Cardiovascular calcification in end stage renal disease. Contrib Nephrol 2005;149:272–278.
14.
Amann K, Ritz C, Adamczak M, Ritz E: Why is coronary heart disease of uraemic patients so frequent and so devastating? Nephrol Dial Transplant 2003;18:631–640.
15.
Schwarz U, Buzello M, Ritz E, Stein G, Raabe G, Wiest G, Mall G, Amann K: Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 2000;15:218–223.
16.
Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ: Atherothrombosis and high-risk plaque. 1. Evolving concepts. J Am Coll Cardiol 2005;46:937–954.
17.
Laukkanen MO, Kivela A, Rissanen T, Rutanen J, Karkkainen MK, Leppanen O, Brasen JH, Yla-Herttuala S: Adenovirus-mediated extracellular superoxide dismutase gene therapy reduces neointima formation in balloon-denuded rabbit aorta. Circulation 2002;106:1999–2003.
18.
Laszik ZG, Zhou XJ, Ferrell GL, Silva FG, Esmon CT: Down-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis. Am J Pathol 2001;159:797–802.
19.
Yoshii Y, Okada Y, Sasaki S, Mori H, Oida K, Ishii H: Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences. Med Electron Microsc 2003;36:165–172.
20.
Tohda G, Oida K, Okada Y, Kosaka S, Okada E, Takahashi S, Ishii H, Miyamori I: Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1998;18:1861–1869.
21.
Stenina OI, Krukovets I, Wang K, Zhou Z, Forudi F, Penn MS, Topol EJ, Plow EF: Increased expression of thrombospondin-1 in vessel wall of diabetic Zucker rat. Circulation 2003;107:3209–3215.
22.
Wu-Wong JR, Nakane M, Ma J: Effects of vitamin D analogs on the expression of plasminogen activator inhibitor-1 in human vascular cells. Thromb Res, in press.
23.
Nordt TK, Peter K, Ruef J, Kubler W, Bode C: Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease. Thromb Haemost 1999;82:14–18.
24.
Kim AY, Walinsky PL, Kolodgie FD, Bian C, Sperry JL, Deming CB, Peck EA, Shake JG, Ang GB, Sohn RH, Esmon CT, Virmani R, Stuart RS, Rade JJ: Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure. Circ Res 2002;90:205–212.
25.
Raugi GJ, Mullen JS, Bark DH, Okada T, Mayberg MR: Thrombospondin deposition in rat carotid artery injury. Am J Pathol 1990;137:179–185.
26.
Vaughan DE: PAI-1 and atherothrombosis. J Thromb Haemost 2005;3:1879–1883.
27.
Adams JC, Lawler J: The thrombospondins. Int J Biochem Cell Biol 2004;36:961–968.
28.
Shah PK: Thrombogenic risk factors for atherothrombosis. Rev Cardiovasc Med 2006;7:10–16.
29.
Waugh JM, Yuksel E, Li J, Kuo MD, Kattash M, Saxena R, Geske R, Thung SN, Shenaq SM, Woo SL: Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circ Res 1999;84:84–92.
30.
Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T, Hayashi H, Yamada Y, Endoh F, Fujimura M, Yoshida T, Yamaguchi H, Hashizume S, Kato M, Yoshimura K, Yamamoto Y, Kato S, Matsumoto T: Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem 2004;279:35798–35802.
31.
Koyama T, Shibakura M, Ohsawa M, Kamiyama R, Hirosawa S: Anticoagulant effects of 1α,25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes. Blood 1998;92:160–167.
32.
Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R: 1α,25-dihydroxyvitamin D(3) and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL. Circulation 2000;102:2867–2872.
33.
Petrie MS, Harrell TE, Schwartz GG, Sane DC: Production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells: differential responses to calcitriol and paricalcitol. J Thromb Haemost 2004;2:2266–2267.
34.
Sajid M, Hu Z, Guo H, Li H, Stouffer GA: Vascular expression of integrin-associated protein and thrombospondin increase after mechanical injury. J Investig Med 2001;49:398–406.
35.
Bailie GR, Johnson CA: Comparative review of the pharmacokinetics of vitamin D analogues. Semin Dial 2002;15:352–357.
36.
Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ: 25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells. Kidney Int 2006;70:654–659.
37.
Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF: Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 1998;7:391–395.
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.