Department of Medicine/Division of Cardiovascular Medicine, School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, State University of New York at Buffalo, Buffalo, NY 14203, USA.
Clin Transl Med. 2014 Jun 14;3:14. doi: 10.1186/2001-1326-3-14. eCollection 2014.
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.
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.
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.
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.
趋化因子（CX3CL1）促进淋巴细胞和单核细胞向炎症组织迁移和黏附。先前的研究表明 CX3CL1 在动脉粥样硬化中起作用。在没有已知冠状动脉疾病的人类受试者中，炎症细胞因子、胆固醇和 CX3CL1 水平之间的关系尚未得到很好的描述。我们研究的目的是评估基线 CX3CL1 水平，并在他汀类药物调节胆固醇水平后，确定 CX3CL1 是否与胆固醇水平或炎症刺激有关。
我们对没有已知冠状动脉疾病的人类受试者进行了一项盲法、随机假设生成研究，这些受试者先后接受了三种不同效力的他汀类药物治疗。测量趋化因子（CX3CL1）、GM-CSF、VEGF-A、其他趋化因子和脂质水平。使用实时 PCR 研究 LDL 胆固醇和 TNFα 在培养的人内皮细胞中诱导 CX3CL1 的机制。
他汀类药物治疗降低了总胆固醇和 LDL 胆固醇水平，正如预期的那样。与未用他汀类药物治疗的对照组（89.9±18.5pg/mL）相比，使用阿托伐他汀（60.0±7.8pg/mL）、普伐他汀（54.2±7.0pg/mL）和瑞舒伐他汀（65.6±7.3pg/mL）治疗后，CX3CL1 水平显著降低（χ(2)(2)=17.4，p≤0.001）。胆固醇不是 CX3CL1 的已知调节剂。我们发现 GM-CSF（r(2) = 0.524；p<0.005）和 VEGF-A（r(2) = 0.4；p<0.005）水平与 CX3CL1 高度正相关。总胆固醇（r(2) = 0.086）和 LDL 胆固醇（r(2) = 0.059）水平与 CX3CL1 水平弱相关。最后，我们测试了 LDL 胆固醇是否可以在人内皮细胞中诱导 CX3CL1、GM-CSF 和 VEGF-A，而不是 TNFα。LDL 胆固醇本身仅导致 CX3CL1 和 GM-CSF 轻度、非显著增加，而 TNFα 导致超过 10 倍的诱导。
我们的研究结果表明，虽然他汀类药物可抑制 CX3CL1 水平，但炎症细胞因子可能是 CX3CL1 水平的主要调节剂，而不是胆固醇本身。需要在更大的患者人群中进行更多研究来证实这些发现，确定 CX3CL1 水平是否反映炎症水平，并可能在预测动脉粥样硬化疾病事件中增加标准危险因素。
