TY - JOUR
T1 - 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
AU - Clancy, Paula
AU - Koblar, Simon A.
AU - Golledge, Jonathan
N1 - Funding Information:
We would like to acknowledge the Queensland Tropical Health Alliance (QTHA) and the Australian Institute of Tropical Health and Medicine (AITHM) for their support of our research. This work was supported by grants from the Australian National Health and Medical Research Council (NHMRC; 1011649 , 1003707 ). JG holds a Practitioner Fellowship from the NHMRC ( 1019921 ) and a Senior Clinical Research Fellowship from the Office of Medical research , Queensland Government. These funding bodies played no role in the production of this manuscript.
PY - 2014/9
Y1 - 2014/9
N2 - 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 invitro 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.
AB - 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 invitro 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.
KW - Angiotensin II
KW - Angiotensin receptor blocker
KW - Anti-Inflammatory
KW - Atheroma
KW - Cytokine
KW - Extracellular signal regulated kinase
UR - http://www.scopus.com/inward/record.url?scp=84905843088&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2014.06.011
DO - 10.1016/j.atherosclerosis.2014.06.011
M3 - Article
C2 - 25016365
AN - SCOPUS:84905843088
SN - 0021-9150
VL - 236
SP - 108
EP - 115
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -