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

Abstract

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.

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Thus, telmisartan prevented hydronephrosis development after unilateral ureteral obstruction in AT1R knockout mouse, an effect that was partly mimicked by losartan and blocked by GW9662 (Kusunoki et al, 2012). The telmisartaninduced expression of ATP binding cassette transporters A1 and G1 and of the scavenger receptor class B type 1 in THP-1 was abolished by PPAR-g siRNA in murine (Nakaya et al, 2007;Matsumura et al, 2011) and human macrophages (Pang et al, 2012). siRNA-induced PPAR-g knockdown abolished the ability of telmisartan to delay endothelial senescence during repeated passaging (Scalera et al, 2008).…”

“…In murine macrophages telmisartan but not losartan, olmesartan, or valsartan activated PPAR-g (Matsumura et al, 2011). PPAR-g activation by telmisartan was also shown in human macrophages (Pang et al, 2012). Site-directed mutagenesis studies using reporter gene readouts have indicated that the binding of telmisartan to PPAR-g has distinct structural requirements compared with that of the thiazolidinediones (Tagami et al, 2009).…”

“…In murine macrophages, telmisartan induced expression of ATP binding cassette transporters A1 and G1 and of CD36, an effect blocked by PPAR-g siRNA (Matsumura et al, 2011). However, it should be noted that some ARBs may affect the expression of PPAR-g target genes in mice in vivo (Iwai et al, 2007) or in human macrophages in vitro (Pang et al, 2012) without being agonists at the receptor. Taken together these findings demonstrate that some ARBs can bind to and activate PPAR-g.…”

Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

“…7) Thus, apart from being a major vasopressor effector of the renin-angiotensin system, ARBs are probably good candidate drugs for inflammation.…”

Crystal Structure, Thermal Behavior and UV Spectroscopy of 6-Chloro-2-(furan-2-yl)-4-oxo-4H-chromen-3-yl Acetate

“…Flavonoids are also recognized moiety for antifungal, cytotoxic, neuroprotective and HIVinhibitory antimicrobial and antifungal properties [6][7][8][9][10][11][12][13] . The synthesis, spectral study and biological activity significance for flavone molecule 6-chloro-2-(furan-2-yl)-4-oxo-4H-chromen-3-yl acetate was reported [14][15][16] . In this work, we report the crystallographic studies to have more insight view of molecular structure and physical property of title compound.…”