Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

An, Jianbo; Nakajima, Toshiaki; Kuba, Keiji; Kimura, Akinori

doi:10.1038/hr.2010.79

Cited by 57 publications

(56 citation statements)

References 27 publications

(31 reference statements)

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“…The effects of telmisartan compared well with those of the PPARγ agonist troglitazone [34]. All ARBs tested inhibited LPS-induced pro-inflammatory gene expression in THP-1 cells, which is consistent with the recent report of anti-inflammatory effects of losartan through a PPARγ-dependent mechanism [35]. This order of potency parallels the reported PPARγ agonist activity of the ARBs tested [6,12].…”

Section: Discussionsupporting

confidence: 78%

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Pang

Benický

Wang

et al. 2012

Journal of Hypertension

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Objective Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPARγ activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARγ gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-κB activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-α, inhibitor of κB-α, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARγ target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARγ antagonism and PPARγ gene silencing. Anti-inflammatory effects of ARBs correlated with their PPARγ agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a major extent through the PPARγ activation pathway and may be beneficial for the treatment of cardiovascular and metabolic disorders in which inflammation plays a major role.

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Section: Discussionsupporting

confidence: 78%

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Pang

Benický

Wang

et al. 2012

Journal of Hypertension

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“…We previously found that macrophage levels were enhanced in Pan02 tumors grown in SPARC−/− mice [23]. Losartan, which has been shown to inhibit inflammatory signaling in macrophages [51] promoted an increase in the M2∶M1 macrophage ratio in tumors grown in SPARC-deficient animals. Losartan treatment did however, negate the increase in Treg recruitment observed in tumors grown in the absence of host SPARC.…”

Section: Discussionmentioning

confidence: 92%

Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

et al. 2012

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Pancreatic adenocarcinoma, a desmoplastic disease, is the fourth leading cause of cancer-related death in the Western world due, in large part, to locally invasive primary tumor growth and ensuing metastasis. SPARC is a matricellular protein that governs extracellular matrix (ECM) deposition and maturation during tissue remodeling, particularly, during wound healing and tumorigenesis. In the present study, we sought to determine the mechanism by which lack of host SPARC alters the tumor microenvironment and enhances invasion and metastasis of an orthotopic model of pancreatic cancer. We identified that levels of active TGFβ1 were increased significantly in tumors grown in SPARC-null mice. TGFβ1 contributes to many aspects of tumor development including metastasis, endothelial cell permeability, inflammation and fibrosis, all of which are altered in the absence of stromal-derived SPARC. Given these results, we performed a survival study to assess the contribution of increased TGFβ1 activity to tumor progression in SPARC-null mice using losartan, an angiotensin II type 1 receptor antagonist that diminishes TGFβ1 expression and activation in vivo. Tumors grown in SPARC-null mice progressed more quickly than those grown in wild-type littermates leading to a significant reduction in median survival. However, median survival of SPARC-null animals treated with losartan was extended to that of losartan-treated wild-type controls. In addition, losartan abrogated TGFβ induced gene expression, reduced local invasion and metastasis, decreased vascular permeability and altered the immune profile of tumors grown in SPARC-null mice. These data support the concept that aberrant TGFβ1-activation in the absence of host SPARC contributes significantly to tumor progression and suggests that SPARC, by controlling ECM deposition and maturation, can regulate TGFβ availability and activation.

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“…(iii) Losartan could exert some of its effect through AT 1 R-independent mechanisms. In this regard, it has been previously reported that losartan inhibits LPS-induced pro-inflammatory gene expression in macrophages by activating the PPARγ (peroxisome-proliferator-activated receptor γ ) pathway rather than by the competitive inhibition of AT 1 R binding to AngII [85]. (iv) Losartan and Ang-(1-7) improve muscle strength in animal models of Duchenne muscular dystrophy through the inhibition of the TGF-β1 signalling pathway [37,86].…”

Section: Discussionmentioning

confidence: 95%

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

et al. 2015

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Skeletal muscle atrophy induced during sepsis syndrome produced by endotoxin in the form of LPS (lipopolysaccharide), is a pathological condition characterized by the loss of strength and muscle mass, an increase in MHC (myosin heavy chain) degradation, and an increase in the expression of atrogin-1 and MuRF-1 (muscle-specific RING-finger protein 1), two ubiquitin E3 ligases belonging to the ubiquitin-proteasome system. Ang-(1-7) [Angiotensin-(1-7)], through its Mas receptor, has beneficial effects in skeletal muscle. We evaluated in vivo the role of Ang-(1-7) and Mas receptor on the muscle wasting induced by LPS injection into C57BL/10J mice. In vitro studies were performed in murine C2C12 myotubes and isolated myofibres from EDL (extensor digitorum longus) muscle. In addition, the participation of p38 MAPK (mitogen-activated protein kinase) in the Ang-(1-7) effect on the LPS-induced muscle atrophy was evaluated. Our results show that Ang-(1-7) prevents the decrease in the diameter of myofibres and myotubes, the decrease in muscle strength, the diminution in MHC levels and the induction of atrogin-1 and MuRF-1 expression, all of which are induced by LPS. These effects were reversed by using A779, a Mas antagonist. Ang-(1-7) exerts these anti-atrophic effects at least in part by inhibiting the LPS-dependent activation of p38 MAPK both in vitro and in vivo. We have demonstrated for the first time that Ang-(1-7) counteracts the skeletal muscle atrophy induced by endotoxin through a mechanism dependent on the Mas receptor that involves a decrease in p38 MAPK phosphorylation. The present study indicates that Ang-(1-7) is a novel molecule with a potential therapeutic use to improve muscle wasting during endotoxin-induced sepsis syndrome.

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Losartan inhibits LPS-induced inflammatory signaling through a PPARγ-dependent mechanism in human THP-1 macrophages

Cited by 57 publications

References 27 publications

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

Losartan Slows Pancreatic Tumor Progression and Extends Survival of SPARC-Null Mice by Abrogating Aberrant TGFβ Activation

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

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