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Blood, 1 July 2006, Vol. 108, No. 1, pp. 192-199. Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2006-01-0094. This Article Full Text Full Text (PDF) All Versions of this Article: 2006-01-0094v1 108/1/192    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shariat-Madar, Z. Articles by Schmaier, A. H. Search for Related Content PubMed PubMed Citation Articles by Shariat-Madar, Z. Articles by Schmaier, A. H. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin Zia Shariat-Madar, Fakhri Mahdi, Mark Warnock, Jonathon W. Homeister, Sujata Srikanth, Yelena Krijanovski, Laine J. Murphey, Ayad A. Jaffa, and Alvin H. Schmaier Hematology/Oncology Division, Department of Internal Medicine, and the Department of Pathology, University of Michigan, Ann Arbor, MI; the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN; and the Department of Internal Medicine, Medical University of South Carolina, Charleston, SC. Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor knockout (KO) mice (BKB2R-/-) have increased thrombosis risk. Paradoxically, the BKB2R-/- mice have long bleeding times and delayed carotid artery thrombosis, 78 ± 6.7 minutes, versus 31 ± 2.7 minutes in controls. The mechanism(s) for thrombosis protection was sought. In BKB2R-/- plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R-/- mice have elevated BK 1-5 (160 ± 75 fmol/mL, vs 44 ± 29 fmol/mL in controls) and angiotensin II (182 ± 41 pg/mL, vs 49 ± 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R-/- mice have elevated plasma 6-keto-PGF1 (666 ± 232 ng/mL, vs 23 ± 5.3 ng/mL in controls) and serum nitrate (61 ± 5.3 µM, vs 24 ± 1.8 µMin controls). Treatment with L-NAME (NG-mono-methyl-L-arginine ester) or nimesulide shortens the thrombosis time. BKB2R-/- mice have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1. The long bleeding times in BKB2R-/- mice also correct with L-NAME and nimesulide therapy. In BKB2R-/- mice, angiotensin II binding to an overexpressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems. (Blood. 2006;108:192-199) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Is the plasma kallikrein-kinin system antithrombotic? Robert W. Colman Blood 2006 108: 1-2. [Full Text] [PDF] This article has been cited by other articles: C. Kleinschnitz, S. Braeuninger, M. Pham, M. Austinat, I. Nolte, T. Renne, B. Nieswandt, M. Bendszus, and G. Stoll Blocking of Platelets or Intrinsic Coagulation Pathway-Driven Thrombosis Does Not Prevent Cerebral Infarctions Induced by Photothrombosis Stroke, April 1, 2008; 39(4): 1262 - 1268. [Abstract] [Full Text] [PDF] S. Merkulov, W.-M. Zhang, A. A. Komar, A. H. Schmaier, E. Barnes, Y. Zhou, X. Lu, T. Iwaki, F. J. Castellino, G. Luo, et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis Blood, February 1, 2008; 111(3): 1274 - 1281. [Abstract] [Full Text] [PDF] D. Gailani and T. Renne Intrinsic Pathway of Coagulation and Arterial Thrombosis Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2507 - 2513. [Abstract] [Full Text] [PDF] Y. Tan, J.-S. Keum, B. Wang, M. B. McHenry, S. R. Lipsitz, and A. A. Jaffa Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1026 - F1035. [Abstract] [Full Text] [PDF] N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

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