Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation

Blood. 2013 Apr 11;121(15):3023-32. doi: 10.1182/blood-2012-09-459156. Epub 2013 Feb 5.

Abstract

Bradykinin B2 receptor-deleted mice (Bdkrb2(-/-)) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2(-/-) also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2(-/-) shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 μM to 15 ± 5 μM), and 6-keto-PGF1α (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2(-/-) platelets express increased NO, guanosine 3',5'-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2(-/-) platelets have reduced collagen-related peptide-induced integrin α2bβ3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2(-/-) hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2(-/-), combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / blood*
  • Angiotensin II / analogs & derivatives
  • Angiotensin II / pharmacology
  • Animals
  • Bleeding Time
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Bone Marrow Transplantation
  • Cyclic AMP / blood
  • Cyclic GMP / blood
  • Epoprostenol / blood*
  • Immunoblotting
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / blood*
  • Peptide Fragments / blood*
  • Peptide Fragments / pharmacology
  • Platelet Aggregation Inhibitors / pharmacology
  • Platelet Membrane Glycoproteins / metabolism*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / blood*
  • Proto-Oncogene Proteins / genetics
  • Receptor, Angiotensin, Type 2 / blood
  • Receptor, Bradykinin B2 / deficiency
  • Receptor, Bradykinin B2 / genetics
  • Receptors, G-Protein-Coupled / blood*
  • Receptors, G-Protein-Coupled / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology
  • Thrombosis / blood
  • Time Factors

Substances

  • 7-Ala-angiotensin (1-7)
  • Peptide Fragments
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 2
  • Receptor, Bradykinin B2
  • Receptors, G-Protein-Coupled
  • Sulfonamides
  • platelet membrane glycoprotein VI
  • Angiotensin II
  • Nitric Oxide
  • Angiotensin I
  • Epoprostenol
  • Cyclic AMP
  • Cyclic GMP
  • angiotensin I (1-7)
  • nimesulide
  • NG-Nitroarginine Methyl Ester