Fractalkine (CX3CL1), GM-CSF and VEGF-a levels are reduced by statins in adult patients.

BACKGROUND: Fractalkine (CX3CL1) promotes migration and adhesion of lymphocytes and monocytes to inflamed tissues. Prior studies show a role for CX3CL1 in atherosclerosis. The relationship between inflammatory cytokines, cholesterol, and CX3CL1 levels in human subjects without known coronary artery disease is not well characterized. The goal of our study was to assess baseline CX3CL1 levels, and after modulation of cholesterol levels by statins to determine if CX3CL1 is linked to cholesterol levels or inflammatory stimuli.

METHODS: We performed a blinded, randomized hypothesis generating study in human subjects without known coronary artery disease treated sequentially with three statins of differing potencies. Fractalkine (CX3CL1), GM-CSF, VEGF-A, other chemokines, and lipid levels were measured. Mechanistic studies of CX3CL1 induction by LDL cholesterol and TNFα in cultured human endothelial cells were performed using real-time PCR.

RESULTS: Therapy with statins reduced total and LDL cholesterol levels as expected. CX3CL1 levels were significantly reduced from no statin control levels (89.9 ± 18.5 pg/mL) after treatment with atorvastatin (60.0 ± 7.8 pg/mL), pravastatin (54.2 ± 7.0 pg/mL) and rosuvastatin (65.6 ± 7.3 pg/mL) (χ (2)(2) = 17.4, p ≤ 0.001). Cholesterol is not a known regulator of CX3CL1. We found GM-CSF (r(2) = 0.524; p < 0.005) and VEGF-A (r(2) = 0.4; p < 0.005) levels were highly and positively correlated with CX3CL1. Total (r(2) = 0.086) and LDL cholesterol (r(2) = 0.059) levels weakly correlated with CX3CL1 levels. Finally, we tested whether LDL cholesterol could induce CX3CL1, GM-CSF, and VEGF-A in human endothelial cells, versus TNFα. LDL cholesterol alone resulted in small, non-significant increases in CX3CL1 and GM-CSF, while TNFα resulted in > 10-fold induction.

CONCLUSIONS: Our findings suggest that while statins suppress CX3CL1 levels, inflammatory cytokines may be the major regulator of CX3CL1 levels rather than cholesterol itself. Additional studies in a larger patient population are needed to confirm these findings, determine if CX3CL1 levels reflect inflammation levels, and potentially add to standard risk factors in prediction of atherosclerotic disease events.