Ablation of angiotensin IV receptor attenuates hypofibrinolysis via PAI-1 downregulation and reduces occlusive arterial thrombosis.
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.


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.
Numaguchi
Yasushi
Y
Department of Medical Science of Proteases, Nagoya University School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan. numa2@med.nagoya-u.ac.jp
Ishii
Masakazu
M
Kubota
Ryuji
R
Morita
Yasuhiro
Y
Yamamoto
Koji
K
Matsushita
Tadashi
T
Okumura
Kenji
K
Murohara
Toyoaki
T
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics / Q000502:physiology*; D006439:Hemodynamics; D006487:Hemostasis; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D058258:Serpin E2; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000378:metabolism
C090830:AT4 receptor; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D010959:Tissue Plasminogen Activator