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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2102.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Ablation of Angiotensin IV Receptor Attenuates Hypofibrinolysis via PAI-1 Downregulation and Reduces Occlusive Arterial Thrombosis

Yasushi Numaguchi; Masakazu Ishii; Ryuji Kubota; Yasuhiro Morita; Koji Yamamoto; Tadashi Matsushita; Kenji Okumura; Toyoaki Murohara

From the Departments of Medical Science of Proteases (Y.N., M.I.), Cardiology (Y.N., M.I., R.K., Y.M., K.O., T. Murohara), Oncology and Hematology (T. Matsushita), and Cardiovascular Medicine (K.O.), Nagoya University School of Medicine, Japan; and the Department of Transfusion Medicine (K.Y.), Nagoya University Hospital, Japan.

Correspondence to Yasushi Numaguchi, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, and Department of Medical Science of Proteases, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. E-mail numa2{at}med.nagoya-u.ac.jp

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.

Knockout mice for insulin-regulated aminopeptidase, identified as the novel angiotensin IV receptor (AT4R), showed accelerated fibrinolysis in an endotoxin-induced microcoagulation model and decreased occlusive thrombosis in a carotid artery double-injury model when compared with control mice, partly because of suppressed induction of plasminogen activator inhibitor type 1 and inhibition of inflammation.

Key Words: AT4R • fibrinolysis • PAI-1 • thrombosis • insulin-regulated aminopeptidase