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

AIM: Angiotensin ⠡(Ang ⠡) 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 ⠡ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with Ang ⠡-induced hypertension. METHODS: TLR4-deficient (Tlr4(lps-d)) and wild-type (WT) mice were randomized into groups treated with Ang ⠡, norepinephrine (NE) or a subdepressor dose of the Ang ⠡receptor blocker irbesartan (IRB) and Ang ⠡ for two weeks. RESULTS: Ang ⠡ 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 ⠡ 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 ⠡ 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 ⠡ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with Ang ⠡ 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 ⠡- induced hypertension.