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• W2461206059 abstract "Abstract Prekallikrein (PK) is the precursor for plasma kallikrein (KK), a serine protease that participates in contact activation. KK promotes inflammation by cleaving high-molecular-weight kininogen (HK) to liberate bradykinin (BK), which binds to the bradykinin B2 receptor (B2R) in the intravascular compartment to induce vasodilation and increase vascular permeability. Recent studies using antisense oligonucleotide (ASO) or gene deficient mice (Klkb1-/-) show that PK deficiency is associated with reduced thrombosis risk without affecting hemostasis. However, the precise in vivo mechanism for thrombosis protection in Klkb1-/- mice is not known. Our investigations show that Klkb1-/- mice have delayed carotid occlusion time on the rose bengal (61.1±2.9 min vs 38.2±3.5 min in WT, p<0.005) and ferric chloride (45.2±9.4 min vs 5.0±1.2 min in WT, p<0.005)) thrombosis model. Klkb1-/- mice have a prolonged APTT (>200 sec vs 38±6 sec in WT) and normal PT (16.9±0.6 sec vs 16.4±0.8 sec in WT). They also have normal platelet count (582.2±38.3X103/µl vs 555.3±34.4X103/µl in WT) and normal tail bleeding time (66±8.9 sec vs 69±3.3 sec in WT). Consistent with a prolonged APTT, Klkb1-/- plasma has defective contact activation-induced thrombin generation time (TGT) (46.28±7.72% AUC as in WT, p<0.001) that partially corrects upon prolonged incubation (75.50±3.88% AUC as in WT, p<0.001). However, in two models of lethal pulmonary thromboembolism induced by contact activation (collagen/epinephrine or long chain polyphosphate), Klkb1-/- mice, unlike F12-/- mice, do not have a survival advantage over WT mice. Histopathology shows equal number of microthrombi in the lungs of polyphosphate-challenged WT and Klkb1-/- mice (34±5 vs 37±5 per visual field, respectively). These data suggest that in Klkb1-/- mice, the mechanism for thrombosis protection is not just reduced contact activation. Klkb1-/- mice have reduced plasma BK levels (0.05±0.01 pg/ml vs 14.03±3.58 pg/ml in WT, p<0.005) and an 80% reduction in renal B2R mRNA. Similar to our recent observation (Figure 1) in Bdkrb2-/- (B2R KO) mice (Blood, 2013:121:3023), Klkb1-/- mice have a compensatory over-expression of renal Mas receptor mRNA and antigen with reduced expression of the angiotensin receptors 1 and 2. Treatment of Klkb1-/- mice with A-779, a Mas antagonist, shortens thrombosis times to normal. Further studies show that the thromboprotective mechanism may be mediated by increased plasma prostacyclin in Klkb1-/- (123±13 pg/ml 6-keto-PGF1α in Klkb1-/- vs 75±10 pg/ml in WT, p<0.05). PGI2 upregulates the vasoprotective transcription factor sirtuin 1 (Sirt1) which downregulates tissue factor (TF). In Klkb1-/- mice, aortic mRNA for Sirt1, Kruppel like factor-2 (Klf2), and thrombomodulin are elevated. In addition, we observe low aortic TF mRNA and decreased TF-induced TGT (89.49±2.53% AUC as in WT, p<0.005) in the Klkb1-/- plasma. Further, consistent with the elevated PGI2 and suppressed TF, Klkb1-/- have delayed thrombus formation in the laser-induced cremaster thrombosis model as detected by CD41 fluorescence. In summary, our investigation reveals a novel mechanism for thrombosis protection in Klkb1-/- mice that is mediated by the receptor Mas and its product prostacyclin through elevation of vasoprotective transcription factors independent of contact activation. These studies along with previous investigations of the Bdkrb2-/- mice suggest that the Mas-Prostacyclin axis is an important modulator of constitutive arterial thrombosis risk. Disclosures: Simon: Cordis/J&J: Consultancy; Janssen/J&J: Consultancy; Medtronic Vascular: Consultancy; Merck: Consultancy; Medtronic Foundation: Research Funding." @default.
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• W2461206059 date "2013-11-15" @default.
• W2461206059 modified "2023-09-27" @default.
• W2461206059 title "Thrombosis Protection In Klkb1-/- (Prekallikrein KO) Mice Is Mediated By Increased Renal Mas Receptor, Plasma Prostacyclin, and Aortic Sirt1" @default.
• W2461206059 doi "https://doi.org/10.1182/blood.v122.21.195.195" @default.
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