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

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 Angll 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 T1r4lps-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 T1r4lps-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.

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

“…MCP-1 inhibition by MCP-1 neutralizing antibody almost completely inhibited the infiltration of macrophages in the pressure-overloaded heart, as well as cardiac hypertrophy and heart failure in the present study, suggesting that MCP-1 working downstream of the PLGF/Flt-1 signaling partially plays a role in the proinflammatory and cardiac maladaptive responses of Flt-1 −/− mice after TAC. In addition, on the basis of previously reported findings that the cardiac expression of MCP-1 may be involved in the progression of maladaptive cardiac remodeling and decompensation, [26][27][28] the present study suggests that the upregulation of MCP-1 in hypertrophied hearts of sFlt-1 −/− mice may be one of the reasons for maladaptive cardiac remodeling.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…ROS, through NADPH oxidase, stimulates CCL2 (MCP1) expression through TLR4, and TLR4 KO mice treated with ANG II are protected from cardiac hypertrophy, whereas the increase in blood pressure is not affected (662). SIRPA is an upstream signaling molecule in this response, as cardiac overexpression of SIRPA protects against cardiac hypertrophy through inhibition of ANG II-induced TLR4/NF-B signaling (436).…”

Protective Roles of Interferon‐γ in Cardiac Hypertrophy Induced by Sustained Pressure Overload

“…In patients with heart failure, the levels of a number of inflammatory cytokines, such as tumor necrosis factor‐α, interleukin‐1β, and interleukin‐6, were shown to be significantly elevated in plasma and circulating leukocytes, as well as in the failing myocardium itself . Moreover, besides these proinflammatory cytokines, additional inflammatory mediators have been proposed to play important roles in the pathogenesis of chronic heart failure arising from maladaptive cardiac remodeling based on the findings obtained from experimental studies and clinical trials …”

“…In patients with heart failure, the levels of a number of inflammatory cytokines, such as tumor necrosis factor-a, interleukin-1b, and interleukin-6, 4,5 were shown to be significantly elevated in plasma and circulating leukocytes, as well as in the failing myocardium itself. 6 Moreover, besides these proinflammatory cytokines, additional inflammatory mediators have been proposed to play important roles in the pathogenesis of chronic heart failure arising from maladaptive cardiac remodeling based on the findings obtained from experimental studies 7,8 and clinical trials. 9 Interferon (IFN)-c is a proinflammatory cytokine and is known as a key player in the immune system because it exerts pleiotropic effects on T cells, NK cells, and macrophages, including enhancements in their antiviral and bactericidal activities and the upregulation of major histocompatibility complex class II expression on macrophages.…”