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Angiotensin-(1-7)/Mas Axis Compensates Absent Bradykinin in Bdkrb2-/- and Klkb1-/- Mice to Regulate Thrombosis Risk

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2014, Doctor of Philosophy, Case Western Reserve University, Pathology.
Part I: Bradykinin B2 receptor deleted mice (Bdkrb2-/-) have delayed carotid artery thrombosis times and prolonged tail bleeding times due to elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide and prostacyclin (Blood 2006;108:192). Bdkrb2-/- also have elevated plasma angiotensin-(1-7) and mRNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 shortens Bdkrb2-/- thrombosis times, bleeding times and lowers plasma nitrate, and 6-keto-PGF1a. Bdkrb2-/- platelets express increased NO, cGMP and cAMP. They have reduced spreading on collagen and peptide GFOGER that is corrected by in vivo A-779 or combined L-NAME and nimesulide treatment. Bdkrb2-/- platelets have reduced CRP-induced integrin a2bß3 activation and P-selectin expression that are corrected by A-779 or nimesulide treatment. Transplantation of wild type bone marrow into Bdkrb2-/- hosts produces platelets with a spreading defect and delayed thrombosis times. Transplantation of Bdkrb2-/- bone marrow into wild type hosts produces platelets with normal spreading and thrombosis times. In Bdkrb2-/- combined AT2R and Mas over-expression produce thrombosis delay due to elevated prostacyclin and NO and reduced collagen-induced platelet activation. in vivo, vascular Mas and AT2R levels increase upon bradykinin B2 receptor deletion to reduce arterial thrombosis risk. Part II: Prekallikrein (PK) is the precursor for plasma kallikrein (KK). Recent studies 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 and ferric chloride thrombosis model. Klkb1-/- plasma has defective contact activation-induced thrombin generation time (TGT) that partially corrects upon prolonged incubation. However, in two models of lethal contact activation-induced pulmonary thromboembolism by collagen/epinephrine or long chain polyphosphate, Klkb1-/- mice, unlike F12-/- mice, do not have a survival advantage over WT mice,. Klkb1-/- mice have reduced plasma BK levels and reduced renal B2R mRNA. Similar to our observation in Bdkrb2-/- mice, Klkb1-/- mice have a compensatory over-expression of renal Mas receptor. Mas antagonist A-779 shortens thrombosis times in Klkb1-/- to normal. The thromboprotective mechanism in Klkb1-/- is mediated by increased plasma prostacyclin producing elevated aortic sirtuin-1 (Sirt1) and KLF-4 with down-regulated aortic tissue factor (TF). Treatment of mouse cardiac endothelial cells (MCECs) with carbaprostacyclin increased mRNA and antigen of Sirt1 and KLF4. In addition, there was decreased endogenous TF-induced TGT in the Klkb1-/- plasma in the presence of infestin-4, a XIIa inhibitor. In summary, our investigation reveals a novel mechanism for thrombosis protection in Klkb1-/- mice independent of contact activation that is mediated by the receptor Mas and its product prostacyclin through elevation of vasoprotective transcription factors. The research in these two animal models demonstrates that Ang-(1-7)/Mas axis is an important regulator of thrombosis risk. Alterations in the KKS influence thrombosis risk through receptors of the RAS.
Alvin Schmaier (Advisor)
George Dubyak (Committee Chair)
Jonathan Stamler (Committee Member)
Eugene Podrez (Committee Member)
Clive Hamlin (Committee Member)
120 p.

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Citations

  • Fang, C. (2014). Angiotensin-(1-7)/Mas Axis Compensates Absent Bradykinin in Bdkrb2-/- and Klkb1-/- Mice to Regulate Thrombosis Risk [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1386329995

    APA Style (7th edition)

  • Fang, Chao. Angiotensin-(1-7)/Mas Axis Compensates Absent Bradykinin in Bdkrb2-/- and Klkb1-/- Mice to Regulate Thrombosis Risk. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1386329995.

    MLA Style (8th edition)

  • Fang, Chao. "Angiotensin-(1-7)/Mas Axis Compensates Absent Bradykinin in Bdkrb2-/- and Klkb1-/- Mice to Regulate Thrombosis Risk." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1386329995

    Chicago Manual of Style (17th edition)