Candesartan inhibits Toll-like receptor expression and activity both in vitro and in vivo

• Published in: Atherosclerosis Vol. 202; no. 1; pp. 76 - 83
• Main Authors: Dasu, Mohan R, Riosvelasco, Andrea C, Jialal, Ishwarlal
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.01.2009; Elsevier
• Subjects: Angiotensin receptor blocker; Animals; Anti-Inflammatory Agents - pharmacology; Antihypertensive Agents - pharmacology; Atherosclerosis (general aspects, experimental research); Benzimidazoles - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; General aspects; Humans; In Vitro Techniques; Inflammation; Lipopeptides - pharmacology; LPS; Male; Medical sciences; Mice; Mice, Inbred C57BL; Monocytes; Monocytes - metabolism; Nuclear factor-kappa B; Phenotype; Reactive Oxygen Species; Tetrazoles - pharmacology; Toll-like receptors; Toll-Like Receptors - metabolism; Vertebrates: cardiovascular system; Nuclear factor-kappa B; Toll-like receptors; Monocytes; Inflammation; Angiotensin receptor blocker; LPS; Imidazole derivatives; Tetrazole derivatives; Monocyte; Candesartan; Peptide hormone; Cardiovascular disease; Biological activity; Vascular disease; Octapeptide; Renin angiotensin system; Biphenyl derivatives; Atherosclerosis; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; Angiotensin II
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2008.04.010

Abstract Introduction Toll-like receptors play an important role in the innate immune system and are found to be crucial in severe diseases like sepsis, atherosclerosis, and arthritis. TLR2 and TLR4 expression is upregulated in the inflammatory diseases. Angiotensin II in addition to stimulating vasoconstriction also induces an increase in ROS and a proinflammatory phenotype via AT1 R. Angiotensin II type-1 receptor blocker (ARB), widely used as an antihypertensive drug, has been reported to also have anti-inflammatory effects. Thus, we investigated whether an ARB exerts anti-inflammatory effects via inhibiting TLR2 and TLR4 expression. Methods and results Monocytes were isolated from healthy human volunteers and treated with the synthetic lipoprotein Pam3CSK4 or LPS in the absence or presence of candesartan. Pretreatment of human monocytes with candesartan significantly decreased Pam3CSK4 or LPS induced TLR2 and TLR4 expression of both mRNA and protein levels ( P < 0.05 vs. control) along with decrease in the activity of NF-κB and the expression of IL-1β, IL-6, TNF-α, and MCP-1. Furthermore, candesartan treated mice show decreased TLR2 and TLR4 expression compared to vehicle control mice. Conclusion Pam3CSK4 and LPS induced TLR2 and TLR4 expression at mRNA and protein levels are inhibited by candesartan both in vitro and in vivo. Thus, we define a novel pathway by which candesartan could induce anti-inflammatory effects.