High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells

The inflammatory chemokines CCL2, CCL5, and CX(3)CL1 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 mu M, final apoA-I concentration), before stimulation with TNF-alpha, inhibited CCL2 (54%), CCL5 (38%), and CX(3)CL1 (33%) protein levels. The chemokine receptors CCR2 (29%) and CX(3)CR1 (22%) were also reduced by rHDLs. Incubation with rHDLs reduced the NF-kappa B subunit p65 in the nucleus (39%) and phosphorylated I kappa B alpha (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-kappa B/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.-Van der Vorst, E. P. C., Vanags, L. Z., Dunn, L. L., Prosser, H. C., Rye, K.-A., Bursill, C. A. High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells. FASEB J. 27, 1413-1425 (2013). www.fasebj.org