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

Clancy, Paula, Koblar, Simon A., and Golledge, Jonathan (2014) 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. Atherosclerosis, 236 (1). pp. 108-115.

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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.

Item ID: 35430
Item Type: Article (Research - C1)
ISSN: 1879-1484
Keywords: anti-inflammatory; angiotensin II; angiotensin receptor blocker; extracellular signal regulated kinase; atheroma; cytokine
Funders: Queensland Tropical Health Alliance (QTHA), Australian Institute of Tropical Health and Medicine (AITHM), National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC 1011649, NHMRC 1003707, NHMRC 1019921
Date Deposited: 25 Sep 2014 00:48
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110299 Cardiovascular Medicine and Haematology not elsewhere classified @ 80%
11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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