Increased levels of CCR7 ligands in carotid atherosclerosis: different effects in macrophages and smooth muscle cells. (11th February 2014)

• Record Type: Journal Article
• Authors: Halvorsen, Bente; Dahl, Tuva B.; Smedbakken, Linda M.; Singh, Anjana; Michelsen, Annika E.; Skjelland, Mona; Krohg-Sørensen, Kirsten; Russell, David; Höpken, Uta E.; Lipp, Martin; Damås, Jan K.; Holm, Sverre; Yndestad, Arne; Biessen, Erik A.; Aukrust, Pål
• Is Part Of: Cardiovascular research. Volume 102:Number 1(2014)
• Page Start: 148
• Page End: 156
• Publication Date: 2014-02-11
• Subjects: Atherosclerosis -- Inflammation -- Chemokines -- SMC -- Macrophages; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu036
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: The homeostatic chemokines, CCL19 and CCL21 and their receptor CCR7, have recently been linked to atherogenesis. We investigated the expression of CCL19/CCL21/CCR7 in carotid atherosclerosis as well as the ability of these chemokines to modulate lipid accumulation in macrophages and vascular smooth muscle cell (SMC) phenotype. Methods and results: Our major findings were: (i) patients with carotid atherosclerosis ( n = 158) had increased plasma levels of CCL21, but not of CCL19, compared with controls ( n = 20), with particularly high levels in symptomatic ( n = 99) when compared with asymptomatic ( n = 59) disease. (ii) Carotid plaques showed markedly increased mRNA levels of CCL21 and CCL19 in symptomatic ( n = 14) when compared with asymptomatic ( n = 7) patients, with CCR7 localized to macrophages and vascular SMC (immunohistochemistry). (iii) In vitro, CCL21, but not CCL19, increased the binding of modified LDL and promoted lipid accumulation in THP-1 macrophages. (iv) CCL19, but not CCL21, increased proliferation and release and activity of matrix metalloproteinase (MMP) 1 in vascular SMC. (v) The differential effects of CCL19 and CCL21 in macrophages and SMC seem to be attributable to divergent signalling pathways, with CCL19-mediated activation of AKT in SMC- and CCL21-mediated activation of extracellular signal-regulated kinase 1/2 in macrophages. Conclusion: CCL19 and CCL21 are up-regulated in carotid atherosclerosis. The ability of CCL21 to promote lipid accumulation in macrophages and of CCL19 to induce proliferation and MMP-1 expression in vascular SMC could contribute to their pro-atherogenic potential.