Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4
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- Matsuda Susumu
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
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- Umemoto Seiji
- Center for Clinical Research, Yamaguchi University Hospital
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- Yoshimura Koichi
- Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine
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- Itoh Shinichi
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
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- Murata Tomoaki
- Institute of Experimental Animals, Science Research Center, Yamaguchi University
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- Fukai Tohru
- Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, University of Illinois at Chicago
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- Matsuzaki Masunori
- Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine
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Aim: Angiotensin Ⅱ(Ang Ⅱ) produces reactive oxygen species (ROS), thus contributing to the development of cardiac hypertrophy and subsequent heart failure, and stimulates the expression of monocyte chemoattractant protein-1 (MCP-1). In addition, Toll-like receptor 4 (TLR4) is involved in the upregulation of MCP-1. In order to clarify whether TLR4 is involved in the onset of cardiac dysfunction caused by Ang Ⅱ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with Ang Ⅱ-induced hypertension.<br>Methods: TLR4-deficient (Tlr4lps-d) and wild-type (WT) mice were randomized into groups treated with Ang Ⅱ, norepinephrine (NE) or a subdepressor dose of the Ang Ⅱreceptor blocker irbesartan (IRB) and Ang Ⅱ for two weeks.<br>Results: Ang Ⅱ and NE similarly increased systolic blood pressure in all drug-treated groups compared to that observed in the control group among both WT and Tlr4lps-d mice (p＜0.05). In the WT mice, Ang Ⅱ induced cardiac hypertrophy as well as vascular remodeling and perivascular fibrosis of the intramyocardial arteries and monocyte/macrophage infiltration in the heart (p＜0.05). Furthermore, Ang Ⅱ treatment decreased the left ventricular diastolic function and resulted in a greater left ventricular end-systolic dimension (p＜0.05) in addition to producing a five-fold increase in the NADPH oxidase activity, ROS content and MCP-1 expression (p＜0.05). In contrast, the Tlr4lps-d mice showed little effects of Ang Ⅱ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with Ang Ⅱ alone. NE produced little effect on any of the indices in either the WT or Tlr4lps-d mice.<br>Conclusions: TLR4 may be involved in the processes underlying the increased oxidative stress, selectively activated MCP-1 expression and cardiac hypertrophy and dysfunction seen in cases of Ang Ⅱ- induced hypertension.
収録刊行物
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- Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ
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Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ 22 (8), 833-844, 2015
一般社団法人 日本動脈硬化学会