Ablation of Angiotensin IV Receptor Attenuates Hypofibrinolysis via PAI-1 Downregulation and Reduces Occlusive Arterial Thrombosis
Ablation of Angiotensin IV Receptor Attenuates Hypofibrinolysis via PAI-1 Downregulation and Reduces Occlusive Arterial Thrombosis
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DOI：
10.1161/atvbaha.109.195057
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发表时间：
2009-12-01
影响因子：
8.7
通讯作者：
Murohara, Toyoaki
中科院分区：
文献类型：
--
作者：
Numaguchi, Yasushi;Ishii, Masakazu;Murohara, Toyoaki
目的：纤溶活性降低与不良心血管事件相关。虽然胰岛素调节的氨基肽酶（IRAP）最近被确定为血管紧张素（Ang） IV受体（AT4R），但AngII远端的AngIV-AT4R信号在纤溶过程中对1型纤溶酶原激活物抑制剂（PAI-1）的激活和随后血栓形成的影响尚不清楚。方法与结果：为了确定AngIV是否会通过PAI-1激活抑制纤维蛋白溶解，促进血栓形成，我们利用IRAP基因敲除小鼠（IRAP(-/-)）评估血栓形成模型的纤维蛋白溶解程度，并研究血管损伤后AT4R的作用。在对照小鼠内皮细胞（WT; C57Bl6/J）中，AngII和AngIV处理均以剂量依赖的方式增加PAI-1 mRNA的表达，而在IRAP（-/-）小鼠内皮细胞中，这种反应被减弱。与WT小鼠相比，IRAP（-/-）小鼠颈动脉中fecl3诱导的血栓形成受到抑制。同样，在颈动脉结扎和袖带放置模型中，IRAP（-/-）小鼠在手术后7天表现出纤维蛋白溶解加速，在28天表现出闭塞性血栓形成减少和负重构。结论- angiv - at4r信号在血管损伤后纤溶及动脉血栓形成过程中起关键作用。AT4R可能是治疗心血管疾病的新靶点。（中国生物医学杂志。2009;29:2102-2108）
Objectives-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. FeCl3-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. (Arterioscler Thromb Vasc Biol. 2009;29:2102-2108.)