Ananyeva N M, Tjurmin A V, Berliner J A, Chisolm G M, Liau G, Winkles J A, Haudenschild C C
Department of Experimental Pathology, Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):445-53. doi: 10.1161/01.atv.17.3.445.
Fibroblast growth factor-1 (FGF-1) and lipoproteins play an important role in atherogenesis. In the present study, we explored a possible mechanism by which abnormal lipid metabolism could be linked to the proliferative aspects of the disease. We tested oxidized LDL (oxLDL) as a possible pathophysiological mediator of the release of FGF-1, using FGF-1-transfected mouse NIH 3T3 cells and FGF-1-transfected rabbit smooth muscle cells, and compared it with the release caused by elevated temperature. Immunoblot analysis showed that oxLDL induced the release of FGF-1 in a concentration-dependent manner from 10 to 100 micrograms/mL. The effect correlated with the extent of oxidative modification of LDL and was maximal within 4 hours of exposure of cells to oxLDL. In contrast to the temperature stress-induced FGF-1 secretion pathway, FGF-1 released in response to oxLDL (1) appeared in the conditioned medium as a monomer, (2) appeared independently of the presence of either actinomycin D or cycloheximide, and (3) was neither enhanced nor inhibited by brefeldin A. We did not detect cell loss, significant morphological changes, changes in growth characteristics, or other indications of lethal toxicity in oxLDL-treated cells. Although the level of lactate dehydrogenase activity was elevated after oxLDL exposure, the calculations showed that > 90% of the FGF-1 was released by viable cells. We propose that oxLDL-induced FGF-1 release is mediated by sublethal and apparently transient changes in cell membrane permeability. In the environment of an atherosclerotic lesion, oxLDL-induced FGF-1 release may be among the mediators of endothelial and smooth muscle cell proliferation.
成纤维细胞生长因子-1（FGF-1）和脂蛋白在动脉粥样硬化形成过程中发挥着重要作用。在本研究中，我们探讨了异常脂质代谢可能与该疾病增殖方面相关联的一种潜在机制。我们使用转染了FGF-1的小鼠NIH 3T3细胞和转染了FGF-1的兔平滑肌细胞，测试了氧化型低密度脂蛋白（oxLDL）作为FGF-1释放的一种可能病理生理介质，并将其与高温导致的释放情况进行比较。免疫印迹分析表明，oxLDL以浓度依赖的方式诱导FGF-1从10至100微克/毫升释放。该效应与LDL的氧化修饰程度相关，并且在细胞暴露于oxLDL的4小时内达到最大值。与温度应激诱导的FGF-1分泌途径不同，响应oxLDL释放的FGF-1：（1）以单体形式出现在条件培养基中；（2）其出现与放线菌素D或环己酰亚胺的存在无关；（3）布雷菲德菌素A对其既无增强作用也无抑制作用。我们在oxLDL处理的细胞中未检测到细胞损失、明显的形态变化、生长特性改变或其他致死毒性迹象。尽管oxLDL暴露后乳酸脱氢酶活性水平升高，但计算表明>90%的FGF-1是由活细胞释放的。我们提出，oxLDL诱导的FGF-1释放是由细胞膜通透性的亚致死性且明显短暂的变化介导的。在动脉粥样硬化病变环境中，oxLDL诱导的FGF-1释放可能是内皮和平滑肌细胞增殖的介质之一。
