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Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis.
- Source :
-
Peptides [Peptides] 2013 Aug; Vol. 46, pp. 53-63. Date of Electronic Publication: 2013 May 31. - Publication Year :
- 2013
-
Abstract
- Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT₁ receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT₁ receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1β and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Angiotensin I biosynthesis
Animals
Arthritis, Rheumatoid drug therapy
Cell Adhesion drug effects
Chemokine CXCL1 biosynthesis
Disease Models, Animal
Female
Hyperalgesia drug therapy
Inflammation drug therapy
Interleukin-1beta biosynthesis
Leukocyte Rolling drug effects
Male
Mice
Mice, Inbred C57BL
Neutrophil Infiltration drug effects
Peptide Fragments biosynthesis
Proto-Oncogene Mas
Proto-Oncogene Proteins metabolism
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 metabolism
Receptors, G-Protein-Coupled metabolism
Tumor Necrosis Factor-alpha biosynthesis
Angiotensin II Type 1 Receptor Blockers pharmacology
Anti-Inflammatory Agents, Non-Steroidal pharmacology
Arthritis, Experimental drug therapy
Losartan pharmacology
Receptor, Angiotensin, Type 1 drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5169
- Volume :
- 46
- Database :
- MEDLINE
- Journal :
- Peptides
- Publication Type :
- Academic Journal
- Accession number :
- 23727291
- Full Text :
- https://doi.org/10.1016/j.peptides.2013.05.012