| First Author | Numaguchi Y | Year | 2009 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 29 |
| Issue | 12 | Pages | 2102-8 |
| PubMed ID | 19745198 | Mgi Jnum | J:167796 |
| Mgi Id | MGI:4880615 | Doi | 10.1161/ATVBAHA.109.195057 |
| Citation | Numaguchi Y, et al. (2009) Ablation of angiotensin IV receptor attenuates hypofibrinolysis via PAI-1 downregulation and reduces occlusive arterial thrombosis. Arterioscler Thromb Vasc Biol 29(12):2102-8 |
| abstractText | OBJECTIVE: Reduced fibrinolytic activity is associated with adverse cardiovascular events. Although insulin-regulated aminopeptidase (IRAP) was recently identified as the angiotensin (Ang) IV receptor (AT4R), the impact of AngIV-AT4R signaling distal to AngII on the activation of type-1 plasminogen activator inhibitor (PAI-1) in the fibrinolytic process and subsequent formation of thrombosis remains unclarified. METHODS AND RESULTS: To determine whether AngIV would inhibit fibrinolysis via PAI-1 activation and promote thrombosis, we evaluated the degree of fibrinolysis in thrombosis models and investigated the roles of AT4R after vascular injury using IRAP knockout mice (IRAP(-/-)). In endothelial cells from control mice (WT; C57Bl6/J), both AngII and AngIV treatments increased PAI-1 mRNA expression in a dose-dependent manner, whereas the response was blunted in endothelial cells from IRAP(-/-) mice. FeCl(3)-induced thrombosis was suppressed in the carotid arteries of IRAP(-/-) mice when compared with WT mice. Similarly, in a model of carotid artery ligation and cuff placement, IRAP(-/-) mice demonstrated accelerated fibrinolysis 7 days after surgery and reduced occlusive thrombosis with negative remodeling at 28 days. CONCLUSIONS: AngIV-AT4R signaling has a key role in fibrinolysis and the subsequent formation of arterial thrombosis after vascular injury. AT4R may be a novel therapeutic target against cardiovascular disease. |
