title: High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells.
abstract: The inflammatory chemokines CCL2, CCL5, and CX₃CL1 stimulate vascular smooth muscle cell (SMC) proliferation. High-density lipoproteins (HDLs) exhibit potent cardioprotective and anti-inflammatory properties. We therefore sought to determine the effect of reconstituted HDLs (rHDLs) on SMC chemokine expression and proliferation and elucidate the mechanisms. Preincubation of primary human SMCs with rHDLs containing apolipoprotein (apo)A-I and phosphatidylcholine (20 μM, final apoA-I concentration), before stimulation with TNF-α, inhibited CCL2 (54%), CCL5 (38%), and CX3CL1 (33%) protein levels. The chemokine receptors CCR2 (29%) and CX3CR1 (22%) were also reduced by rHDLs. Incubation with rHDLs reduced the NF-κB subunit p65 in the nucleus (39%) and phosphorylated IκBα (28%), both regulators of chemokine expression. Furthermore, rHDLs inhibited the upstream signaling proteins phosphoinositide 3-kinase (37%) and phosphorylated Akt (pAkt, 49%). Incubation with rHDLs strikingly suppressed SMC proliferation (84%) and ERK phosphorylation (pERK, 29%). Finally, siRNA knockdown of the scavenger receptor SR-B1 attenuated rHDL-induced inhibition of SMC chemokine expression, p65, and proliferation, indicating that SR-B1 plays a key role in mediating these effects. Thus, rHDLs reduce SMC chemokine expression (via NF-κB/pAkt inhibition) and proliferation (via pERK inhibition). This has important implications for preventing the pathogenesis of neointimal hyperplasia, the main cause of early vein graft/stent failure.
authors.affiliation: Heart Research Institute, Newtown, New South Wales, Australia.
authors.forename: Emiel P C
authors.initials: EP
authors.lastname: van der Vorst
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Vanags
authors.forename: Louise L
authors.initials: LL
authors.lastname: Dunn
authors.forename: Hamish C
authors.initials: HC
authors.lastname: Prosser
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000276:immunology / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054428:Chemokine CX3CL1; D018925:Chemokines; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt