Angiotensin Ⅱ Activates MCP-1 and Induces Cardiac Hypertrophy and Dysfunction via Toll-like Receptor 4.

Abstract

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.

METHODS:

TLR4-deficient (Tlr4(lps-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.

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 Tlr4(lps-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 Tlr4(lps-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 Tlr4(lps-d) mice.

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.

• Authors: Susumu Matsuda, Seiji Umemoto, Koichi Yoshimura, Shinichi Itoh, Tomoaki Murata, Tohru Fukai, Masunori Matsuzaki
• Journal: Journal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 22 Issue 8 Pg. 833-44 (Aug 26 2015) ISSN: 1880-3873 [Electronic] Japan
• PMID: 25752363 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-Agonists
• Angiotensin II Type 1 Receptor Blockers
• Biphenyl Compounds
• Chemokine CCL2
• Tetrazoles
• Toll-Like Receptor 4
• Vasoconstrictor Agents
• Angiotensin II
• Irbesartan
• Norepinephrine

Topics

• Adrenergic alpha-Agonists (pharmacology)
• Angiotensin II (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Biphenyl Compounds (pharmacology)
• Cardiomegaly (etiology)
• Chemokine CCL2 (physiology)
• Hypertension (etiology)
• Irbesartan
• Male
• Mice
• Mice, Inbred BALB C
• Norepinephrine (pharmacology)
• Oxidative Stress (physiology)
• Tetrazoles (pharmacology)
• Toll-Like Receptor 4 (physiology)
• Vasoconstrictor Agents (pharmacology)