Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin.
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.
Shariat-Madar
Zia
Z
Hematology/Oncology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Mahdi
Fakhri
F
Warnock
Mark
M
Homeister
Jonathon W
JW
Srikanth
Sujata
S
Krijanovski
Yelena
Y
Murphey
Laine J
LJ
Jaffa
Ayad A
AA
Schmaier
Alvin H
AH
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*
D043782:Receptor, Bradykinin B2; D009569:Nitric Oxide; D011464:Epoprostenol