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

作者：Fang Chao; Stavrou Evi; Schmaier Alec A; Grobe Nadja; Morris Mariana; Chen Andrew; Nieman Marvin T; Adams Gregory N; LaRusch Gretchen; Zhou Yihua; Bilodeau Matthew L; Mahdi Fakhri; Warnock Mark; Schmaier Alvin H

来源：Blood, 2013, 121(15): 3023-3032.

DOI：10.1182/blood-2012-09-459156

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 mu M to 15 +/- 5 mu M), and 6-keto-PGF(1 alpha) (259 +/- 103 pg/mL to 132 +/- 58 pg/mL). Bdkrb2(-/-) platelets express increased NO, guanosine 3%26apos;,5%26apos;-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 alpha(2b)beta(3) 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.

• 出版日期2013-4-11