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

J Atheroscler Thromb. 2015 Aug 26;22(8):833-44. doi: 10.5551/jat.27292. Epub 2015 Mar 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

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