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

Pubmed ID: 23386129

Pubmed Central ID: PMC3624945

Journal: Blood

Publication Date: April 11, 2013

Affiliation: Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.

MeSH Terms: Animals, Time Factors, Peptide Fragments, Mice, Reverse Transcriptase Polymerase Chain Reaction, Cyclic GMP, Nitric Oxide, Blood Platelets, Immunoblotting, Thrombosis, Platelet Aggregation Inhibitors, Bone Marrow Transplantation, Angiotensin I, Angiotensin II, Bleeding Time, Cyclic AMP, Epoprostenol, Mice, 129 Strain, Mice, Knockout, NG-Nitroarginine Methyl Ester, Platelet Membrane Glycoproteins, Proto-Oncogene Proteins, Receptor, Angiotensin, Type 2, Receptor, Bradykinin B2, Receptors, G-Protein-Coupled, Sulfonamides, Proto-Oncogene Mas

Grants: F32 DK093226, HL052779, HL057346, HL065194, HL112666, R21 HL112666, R01 HL052779, P01 HL057346, R01 HL065194

Authors: Morris M, Fang C, Stavrou E, Schmaier AA, Grobe N, Chen A, Nieman MT, Adams GN, LaRusch G, Zhou Y, Bilodeau ML, Mahdi F, Warnock M, Schmaier AH

Cite As: Fang C, Stavrou E, Schmaier AA, Grobe N, Morris M, Chen A, Nieman MT, Adams GN, LaRusch G, Zhou Y, Bilodeau ML, Mahdi F, Warnock M, Schmaier AH. 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. Epub 2013 Feb 5.

Studies:

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.