Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin
Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin
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DOI：
10.1182/blood-2006-01-0094
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发表时间：
2006-07-01
期刊：
影响因子：
20.3
通讯作者：
Schmaier, Alvin H.
中科院分区：
文献类型：
--
作者：
Shariat-Madar, Zia;Mahdi, Fakhri;Schmaier, Alvin H.
缓激肽（BK）从内皮细胞释放一氧化氮、前列环素和组织纤溶酶原激活物。我们假设BK B2受体敲除（KO）小鼠（BKB 2 R（-/-））具有增加的血栓形成风险。奇怪的是，BKB 2 R（-/-）小鼠的出血时间较长，颈动脉血栓形成延迟，为78 +/- 6.7分钟，而对照组为31 +/- 2.7分钟。探索血栓形成保护机制。在BKB 2 R（-/-）血浆凝血，纤溶和抗凝蛋白是正常的，除了增加前激肽释放酶和减少因子XI。BKB 2 R（-/-）小鼠具有升高的BK 1-5（160 +/- 75 fmol/mL，对照组中为44 +/- 29 fmol/mL）和血管紧张素11（182 +/- 41 pg/mL，对照组中为49 +/- 7 pg/mL）。雷米普利治疗可缩短血管闭塞时间。BKB 2 R（-/-）小鼠的血浆6-酮-PGF（1 α）（666 +/- 232 ng/mL，对照组为23 +/- 5.3 ng/mL）和血清硝酸盐（61 +/- 5.3 μ M，对照组为24 +/- 1.8 μ M）升高。用L-NAME（W-单甲基-L-精氨酸酯）或尼美舒利治疗可缩短血栓形成时间。BKB 2 R-/-小鼠血管紧张素受体2（AT（2）R）mRNA和蛋白表达增加。用AT（2）R拮抗剂PD 123 319治疗，使血栓形成时间和硝酸盐和6-酮-PGF 1 α正常化。BKB 2 R（-/-）小鼠的长出血时间也可以用L-NAME和尼美舒利治疗来纠正。在BKB 2 R（-/-）小鼠中，血管紧张素11与过度表达的AT（2）R结合，通过升高一氧化氮和前列环素促进血栓保护作用。这些研究表明通过血浆激肽释放酶/激肽和肾素血管紧张素系统降低血栓形成风险的途径。
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 11 (182 +/- 41 pg/mL, vs 49 +/- 7 pg/mL in controls). Ramipril treatment shortens vessel occlusion time. BKB2R(-/-) mice have elevated plasma 6-keto-PGF(1 alpha) (666 +/- 232 ng/mL, vs 23 +/- 5.3 ng/mL in controls) and serum nitrate (61 +/- 5.3 mu M, vs 24 +/- 1.8 mu M in controls). Treatment with L-NAME (W-monomethyl-L-arginine ester) or nimesulide shortens the thrombosis time. BKB2R-/- mice have increased angiotensin receptor 2 (AT(2)R) mRNA and protein expression. Treatment with an AT(2)R antagonist, PD123 319, normalizes the thrombosis time and nitrate and 6-keto-PGF1 alpha. The long bleeding times in BKB2R(-/-) mice also correct with L-NAME and nimesulide therapy. In BKB2R(-/-) mice, angiotensin 11 binding to an overexpressed AT(2)R 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.