Lawn R M, Pearle A D, Kunz L L, Rubin E M, Reckless J, Metcalfe J C, Grainger D J
Falk Cardiovascular Research Center, Stanford University, Stanford, California 94305-5246, USA.
J Biol Chem. 1996 Dec 6;271(49):31367-71. doi: 10.1074/jbc.271.49.31367.
Apolipoprotein(a) (apo(a)), the distinguishing protein of atherogenic lipoprotein(a), directs accumulation of the lipoprotein(a) particle to sites in the arterial wall where atherosclerotic lipid lesions develop in man and in transgenic mice expressing human apo(a). It has been proposed that focal apo(a) accumulation in the transgenic mouse vessel wall causes the observed severe local inhibition of transforming growth factor-beta (TGF-beta) activity and the consequent activation of the smooth muscle cells, which subsequently accumulate lipid to form lesions if the mice are fed a high fat diet. We show that blocking formation of these vascular lesions by two independent mechanisms, tamoxifen treatment and increasing high density lipoprotein, also abolishes apo(a) accumulation, inhibition of TGF-beta activity, and activation of smooth muscle cells. The data are consistent with a feedback mechanism in which an initial accumulation of apo(a) inhibits local TGF-beta activity, leading to further accumulation of apo(a). Breaking the feedback loop prevents smooth muscle cell activation and therefore lipid lesion development.
载脂蛋白(a)（apo(a)）是致动脉粥样硬化脂蛋白(a)的特征性蛋白质，在人和表达人apo(a)的转基因小鼠中，它会将脂蛋白(a)颗粒积累到动脉壁中动脉粥样硬化脂质病变发生的部位。有人提出，转基因小鼠血管壁中apo(a)的局部积累会导致观察到的转化生长因子-β（TGF-β）活性受到严重局部抑制，进而激活平滑肌细胞，如果给这些小鼠喂食高脂肪饮食，平滑肌细胞随后会积累脂质形成病变。我们发现，通过两种独立机制（他莫昔芬治疗和增加高密度脂蛋白）阻断这些血管病变的形成，也能消除apo(a)的积累、TGF-β活性的抑制以及平滑肌细胞的激活。这些数据与一种反馈机制一致，即apo(a)的初始积累会抑制局部TGF-β活性，导致apo(a)进一步积累。打破反馈回路可防止平滑肌细胞激活，从而阻止脂质病变的发展。
