title: Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation.
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.
authors: Hematology and Oncology Division, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors: Chao
authors: C
authors: Fang
authors: Evi
authors: E
authors: Stavrou
authors: Alec A
authors: AA
authors: Schmaier
authors: Nadja
authors: N
authors: Grobe
authors: Mariana
authors: M
authors: Morris
authors: Andrew
authors: A
authors: Chen
authors: Marvin T
authors: MT
authors: Nieman
authors: Gregory N
authors: GN
authors: Adams
authors: Gretchen
authors: G
authors: LaRusch
authors: Yihua
authors: Y
authors: Zhou
authors: Matthew L
authors: ML
authors: Bilodeau
authors: Fakhri
authors: F
authors: Mahdi
authors: Mark
authors: M
authors: Warnock
authors: Alvin H
authors: AH
authors: Schmaier
mesh_terms: D000803:Angiotensin I / Q000097:blood*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D011464:Epoprostenol / Q000097:blood*; D015151:Immunoblotting; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000097:blood* / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000097:blood; D043782:Receptor, Bradykinin B2 / Q000172:deficiency / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000097:blood* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood; D013997:Time Factors
chemical_list: C092006:7-Ala-angiotensin (1-7); D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C098341:platelet membrane glycoprotein VI; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; D011464:Epoprostenol; D000242:Cyclic AMP; D006152:Cyclic GMP; C118790:angiotensin I (1-7); C012655:nimesulide; D019331:NG-Nitroarginine Methyl Ester
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