title: Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin.
abstract: 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-PGF1alpha (666 +/- 232 ng/mL, vs 23 +/- 5.3 ng/mL in controls) and serum nitrate (61 +/- 5.3 microM, vs 24 +/- 1.8 microM in 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-PGF1alpha. 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.
authors.affiliation: Hematology/Oncology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Zia
authors.initials: Z
authors.lastname: Shariat-Madar
authors.forename: Fakhri
authors.initials: F
authors.lastname: Mahdi
authors.forename: Mark
authors.initials: M
authors.lastname: Warnock
authors.forename: Jonathon W
authors.initials: JW
authors.lastname: Homeister
authors.forename: Sujata
authors.initials: S
authors.lastname: Srikanth
authors.forename: Yelena
authors.initials: Y
authors.lastname: Krijanovski
authors.forename: Laine J
authors.initials: LJ
authors.lastname: Murphey
authors.forename: Ayad A
authors.initials: AA
authors.lastname: Jaffa
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D000818:Animals; D001760:Bleeding Time; D011464:Epoprostenol / Q000097:blood*; D020869:Gene Expression Profiling; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood*; D043782:Receptor, Bradykinin B2 / Q000097:blood* / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013927:Thrombosis / Q000097:blood*
chemical_list: D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; D011464:Epoprostenol