Abstract
Aim: Angiotensin Ⅱ (AngⅡ) 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 AngⅡ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with AngⅡ-induced hypertension. Methods: TLR4-deficient (Tlr4lps-d) and wild-type (WT) mice were randomized into groups treated with AngⅡ, norepinephrine (NE) or a subdepressor dose of the AngⅡ receptor blocker irbesartan (IRB) and AngⅡ for two weeks. Results: AngⅡ 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, AngⅡ 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, AngⅡ 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 AngⅡ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with AngⅡ alone. NE produced little effect on any of the indices in either the WT or Tlr4lps-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 AngⅡ- induced hypertension.
Original language | English (US) |
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Pages (from-to) | 833-844 |
Number of pages | 12 |
Journal | Journal of Atherosclerosis and Thrombosis |
Volume | 22 |
Issue number | 8 |
DOIs | |
State | Published - Aug 26 2015 |
Externally published | Yes |
Keywords
- Angiotensin II
- Cardiac hypertrophy
- Hypertension
- Monocyte chemoattractant protein-1
- Mouse
- Toll-like receptor 4
ASJC Scopus subject areas
- Internal Medicine
- Cardiology and Cardiovascular Medicine
- Biochemistry, medical