Theilmeier G, De Geest B, Van Veldhoven P P, Stengel D, Michiels C, Lox M, Landeloos M, Chapman M J, Ninio E, Collen D, Himpens B, Holvoet P
Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.
FASEB J. 2000 Oct;14(13):2032-9. doi: 10.1096/fj.99-1029com.
Macrophage infiltration into the subendothelial space at lesion prone sites is the primary event in atherogenesis. Inhibition of macrophage homing might therefore prevent atherosclerosis. Since HDL levels are inversely correlated with cardiovascular risk, their effect on macrophage homing was assessed in apoE-deficient (apoE-/-) mice. Overexpression of human apolipoprotein AI in apoE-/- mice increased HDL levels 3-fold and reduced macrophage accumulation in an established assay of leukocyte homing to aortic root endothelium 3.2-fold (P<0.005). This was due to reduced in vivo betaVLDL oxidation, reduced betaVLDL triggered endothelial cytosolic Ca2+ signaling through PAF-like bioactivity, lower ICAM-1 and VCAM-1 expression, and diminished ex vivo leukocyte adhesion. Adenoviral gene transfer of human PAF-acetylhydrolase (PAF-AH) in apoE-/- mice increased PAF-AH activity 1.5-fold (P<0.001), reduced betaVLDL-induced ex vivo macrophage adhesion 3.5-fold (P<0.01), and reduced in vivo macrophage homing 2.6-fold (P<0.02). These inhibitory effects were observed in the absence of increased HDL cholesterol levels. In conclusion, HDL reduces macrophage homing to endothelium by reducing oxidative stress via its associated PAF-AH activity. This protective mechanism is independent of the function of HDL as cholesterol acceptor. Modulation of lipoprotein oxidation by PAF-AH may prevent leukocyte recruitment to the vessel wall, a key feature in atherogenesis.
巨噬细胞浸润到易损部位的内皮下空间是动脉粥样硬化发生的主要事件。因此，抑制巨噬细胞归巢可能预防动脉粥样硬化。由于高密度脂蛋白（HDL）水平与心血管风险呈负相关，因此在载脂蛋白E缺陷（apoE-/-）小鼠中评估了其对巨噬细胞归巢的影响。在apoE-/-小鼠中过表达人载脂蛋白AI可使HDL水平增加3倍，并在已建立的白细胞归巢至主动脉根内皮的实验中将巨噬细胞积聚减少3.2倍（P<0.005）。这是由于体内β极低密度脂蛋白（βVLDL）氧化减少、βVLDL通过类血小板活化因子（PAF）样生物活性触发的内皮细胞胞质Ca2+信号传导减少、细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）表达降低以及离体白细胞黏附减少。在apoE-/-小鼠中进行人PAF-乙酰水解酶（PAF-AH）的腺病毒基因转移可使PAF-AH活性增加1.5倍（P<0.001），使βVLDL诱导的离体巨噬细胞黏附减少3.5倍（P<0.01），并使体内巨噬细胞归巢减少2.6倍（P<0.02）。在未增加HDL胆固醇水平的情况下观察到了这些抑制作用。总之，HDL通过其相关的PAF-AH活性降低氧化应激，从而减少巨噬细胞向内皮的归巢。这种保护机制独立于HDL作为胆固醇受体的功能。PAF-AH对脂蛋白氧化的调节可能防止白细胞募集到血管壁，这是动脉粥样硬化发生的关键特征。
