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

Abstract

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.

• Authors: Yasushi Numaguchi, Masakazu Ishii, Ryuji Kubota, Yasuhiro Morita, Koji Yamamoto, Tadashi Matsushita, Kenji Okumura, Toyoaki Murohara
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 29 Issue 12 Pg. 2102-8 (Dec 2009) ISSN: 1524-4636 [Electronic] United States
• PMID: 19745198 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AT4 receptor
• Lipopolysaccharides
• RNA, Messenger
• Receptors, Angiotensin
• Serpin E2
• Serpine2 protein, mouse
• Serpins
• Angiotensin II
• angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-
• Tissue Plasminogen Activator

Topics

• Angiotensin II (analogs & derivatives, pharmacology, physiology)
• Animals
• Cells, Cultured
• Disease Models, Animal
• Down-Regulation
• Endothelial Cells (drug effects, metabolism)
• Fibrinolysis (genetics, physiology)
• Hemodynamics
• Hemostasis
• Kidney Glomerulus (drug effects, metabolism)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Knockout
• RNA, Messenger (genetics, metabolism)
• Receptors, Angiotensin (deficiency, genetics, physiology)
• Serpin E2
• Serpins (genetics, metabolism)
• Signal Transduction
• Thrombosis (genetics, pathology, physiopathology, prevention & control)
• Tissue Plasminogen Activator (metabolism)