Choi K H, Kang S W, Lee S W, Lee H Y, Han D S, Kang B S
Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.
Yonsei Med J. 1995 Jul;36(3):251-61. doi: 10.3349/ymj.1995.36.3.251.
In order to investigate the anti-proliferative effect of 3-hydroxy-3-methylglutaryl coenzyme. A reductase inhibitor, we evaluated the effects of lovastatin on DNA replication and the proliferation of rat mesangial and aortic smooth muscle cells, both of which were mesenchymal origin cells. Proliferations were determined by measuring [3H]thymidine uptake, and counting the number of cells. Growth-arrested mesangial and aortic smooth muscle cells were exposed to platelet-derived growth factor (PDGF), endothelin (ET) and angiotensin II (Ang II) to stimulate mitogenesis. All agents exhibited dose-dependent stimulation of [3H] thymidine uptake. PDGF was more potent than the others. Ang II increased [3H] thymidine uptake without demonstrable mitogenic activity. Lovastatin inhibited PDGF (10 ng/ml in mesangial cell, 25 ng/ml in smooth muscle cell)-, ET (10(-7)M)- and Ang II (10(-7)M)-induced [3H] thymidine uptake significantly in a dose-dependent manner in both cells. The increase of cell number in response to PDGF and ET treatment were also inhibited at 10 microM of lovastatin. The inhibitory effect of lovastatin was largely overcome in the presence of exogenous mevalonate at 200 microM, with 75.5% restoration from lovastatin-induced inhibition on PDGF-induced [3H] thymidine uptake in mesangial cells (77.8% in aortic smooth muscle cells). However, the addition of cholesterol did not prevent inhibition by lovastatin. In conclusion, lovastatin had an inhibitory effect on mesangial and aortic smooth muscle cell proliferation, and mevalonate was essential for DNA replication in both types of cells. Lovastatin may reduce glomerular and atherosclerotic injury through an anti-proliferative effect on mesangial and vascular smooth muscle cells, in addition to lowering circulating lipids.
为了研究3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的抗增殖作用，我们评估了洛伐他汀对大鼠系膜细胞和主动脉平滑肌细胞DNA复制及增殖的影响，这两种细胞均为间充质起源细胞。通过测量[³H]胸腺嘧啶核苷摄取量和计数细胞数量来确定细胞增殖情况。将生长停滞的系膜细胞和主动脉平滑肌细胞暴露于血小板衍生生长因子（PDGF）、内皮素（ET）和血管紧张素II（Ang II）以刺激有丝分裂。所有试剂均表现出对[³H]胸腺嘧啶核苷摄取的剂量依赖性刺激作用。PDGF比其他试剂更有效。Ang II增加了[³H]胸腺嘧啶核苷摄取，但未表现出明显的有丝分裂活性。洛伐他汀以剂量依赖性方式显著抑制了PDGF（系膜细胞中为10 ng/ml，平滑肌细胞中为25 ng/ml）、ET（10⁻⁷M）和Ang II（10⁻⁷M）诱导的两种细胞中的[³H]胸腺嘧啶核苷摄取。在10 μM洛伐他汀存在下，对PDGF和ET处理的细胞数量增加也有抑制作用。在200 μM外源性甲羟戊酸存在时，洛伐他汀的抑制作用在很大程度上被克服，系膜细胞中从洛伐他汀诱导的对PDGF诱导的[³H]胸腺嘧啶核苷摄取抑制中恢复了75.5%（主动脉平滑肌细胞中为77.8%）。然而，添加胆固醇并不能阻止洛伐他汀的抑制作用。总之，洛伐他汀对系膜细胞和主动脉平滑肌细胞增殖有抑制作用，甲羟戊酸对这两种细胞的DNA复制至关重要。除了降低循环脂质外，洛伐他汀可能通过对系膜细胞和血管平滑肌细胞的抗增殖作用减轻肾小球和动脉粥样硬化损伤。
