Angiotensin receptor 1 blockade reduces secretion of inflammation associated cytokines from cultured human carotid atheroma and vascular cells in association with reduced extracellular signal regulated kinase expression and activation

• Published in: Atherosclerosis 2014-09, Vol.236 (1), p.108-115
• Main Authors: Clancy, Paula, Koblar, Simon A, Golledge, Jonathan
• Format: Article
• Language: English
• Subjects: 1-Sarcosine-8-Isoleucine Angiotensin II - pharmacology; Aged; Angiotensin II Type 1 Receptor Blockers - pharmacology; Biphenyl Compounds - pharmacology; Cardiovascular; Carotid Arteries - pathology; Cells, Cultured; Chemokines - secretion; Cytokines - secretion; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - secretion; Enzyme Activation - drug effects; Enzyme Induction - drug effects; Female; Humans; Inflammation; Male; MAP Kinase Signaling System - drug effects; Middle Aged; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Osteoprotegerin - secretion; Peptides - pharmacology; Plaque, Atherosclerotic - pathology; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Tetrazoles - pharmacology
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2014.06.011

Abstract Background A number of studies have suggested that angiotensin II (AII) receptor type 1 (ATR1) blocking drugs (ARBs) have anti-inflammatory effects however the mechanisms responsible are poorly investigated. Objective To determine the role of extracellular signal regulated kinase (ERK)1/2 in ARB induced anti-inflammatory effects within human carotid atherosclerosis. Methods Atheroma samples obtained from patients undergoing carotid endarterectomy were cultured with and without ATR1 (irbesartan), ERK1/2 (PD98059), AII ([Sar1 , Ile8 ]-AII) and angiotensin converting enzyme (ACE)2 (DX600) blockade. The in vitro effects of ATR1 and ERK1/2 blockade and exogenous AII on serum stimulated healthy, primary vascular cells were also investigated. Outcome was assessed by measuring cytokine, (interleukin (IL)-6, IL-8, C–C motif chemokine (CCL)2, C-X-C motif chemokine (CXCL)5, osteoprotegerin (OPG), osteopontin (OPN), CXCL16), concentrations in supernatants and phosphorylated ERK1/2 in the tissue lysates using ELISA. ERK1/2 expression in the tissue was assessed using Western blotting. Results Irbesartan reduced concentrations of IL-6, IL-8, CCL2, CXCL5, OPG, OPN and CXCL16 in both atheroma and primary vascular cell culture supernatants. The reduction in cytokine levels in the atheroma supernatant was correlated to a reduction in ERK1/2 expression in the tissue. Inhibition of ERK1/2 downregulated IL-6, IL-8 and CXCL5 in both atheroma and cell culture supernatants. AII and ACE2 blockade had no impact on cytokine or active ERK1/2 levels in the atheroma culture. Conclusion Our findings suggest that ATR1 blockade downregulates atheroma tissue ERK1/2 expression leading to a reduction in cytokine production and that a non-AII agonist ATR1 signalling response may induce expression of these inflammation associated cytokines in the atheroma.