Stiko-Rahm A, Hultgårdh-Nilsson A, Regnström J, Hamsten A, Nilsson J
Department of Internal Medicine, Karolinska Hospital, Stockholm, Sweden.
Arterioscler Thromb. 1992 Sep;12(9):1099-109. doi: 10.1161/01.atv.12.9.1099.
Animal studies have demonstrated that hypercholesterolemia leads to the development of fibromuscular atherosclerotic lesions that are characterized by the intimal accumulation of cholesterol esters in macrophage foam cells and focal proliferation of smooth muscle cells (SMCs). There is now convincing evidence that formation of foam cells occurs as a result of macrophage uptake of oxidized low density lipoprotein (LDL), but the processes linking hypercholesterolemia to activation of SMC growth are less clear. In the present study, we demonstrated that native as well as oxidized LDL stimulates DNA synthesis in cultured human SMCs. Both native and oxidized LDL enhances the expression of platelet-derived growth factor (PDGF) A-chain transcripts in the cells, suggesting that the mitogenic effect of the lipoprotein preparations may be due to activation of autocrine or paracrine PDGF loops. Preincubation of SMCs with native and oxidized LDL also increased the expression of PDGF alpha- and beta-receptors on SMCs and enhanced the responsiveness of the cells to exogenous PDGF. The maximal stimulatory effect of oxidized LDL occurred at a concentration of 3 micrograms/ml, whereas that of native LDL occurred at 10 micrograms/ml, but otherwise no difference was observed between the native and oxidized LDL preparations. The mitogenic effects of LDL disappeared if the cells were exposed to the lipoprotein preparations for more than 4 hours and was also effectively inhibited by superoxide dismutase. The present results suggest that LDL may influence the growth of SMCs by modulating the expression of growth-regulatory genes in the cells.
动物研究表明，高胆固醇血症会导致纤维肌性动脉粥样硬化病变的发展，其特征是巨噬细胞泡沫细胞内膜中胆固醇酯的积累和平滑肌细胞（SMC）的局灶性增殖。现在有令人信服的证据表明，泡沫细胞的形成是巨噬细胞摄取氧化型低密度脂蛋白（LDL）的结果，但将高胆固醇血症与SMC生长激活联系起来的过程尚不清楚。在本研究中，我们证明天然LDL以及氧化型LDL均可刺激培养的人SMC的DNA合成。天然LDL和氧化型LDL均可增强细胞中血小板衍生生长因子（PDGF）A链转录物的表达，这表明脂蛋白制剂的促有丝分裂作用可能是由于自分泌或旁分泌PDGF环的激活。用天然LDL和氧化型LDL对SMC进行预孵育也增加了SMC上PDGFα和β受体的表达，并增强了细胞对外源性PDGF的反应性。氧化型LDL在浓度为3微克/毫升时出现最大刺激作用，而天然LDL在浓度为10微克/毫升时出现最大刺激作用，但除此之外，天然LDL制剂和氧化型LDL制剂之间未观察到差异。如果细胞暴露于脂蛋白制剂超过4小时，LDL的促有丝分裂作用就会消失，并且超氧化物歧化酶也能有效抑制该作用。目前的结果表明，LDL可能通过调节细胞中生长调节基因的表达来影响SMC的生长。
