Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California Davis, Sacramento, California 95817, USA.
Biol Reprod. 2012 Jul 5;87(1):2, 1-6. doi: 10.1095/biolreprod.111.098806. Print 2012 Jul.
Recently we reported that statins, the competitive inhibitors of the key enzyme regulating the mevalonate pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), decrease proliferation of human endometrial stromal (HES) cells. Furthermore, we found that simvastatin treatment reduces the number and the size of endometrial implants in a nude mouse model of endometriosis. The present study was undertaken to investigate the effect of simvastatin on HES cell invasiveness and on expression of selected genes relevant to invasiveness: matrix metalloproteinase 2 (MMP2), MMP3, tissue inhibitor of matrix metalloproteinase 2 (TIMP2), and CD44. Because statin-induced inhibition of HMGCR reduces the production of substrates for isoprenylation-geranylgeranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP)-the effects of GGPP and FPP were also evaluated. Simvastatin induced a concentration-dependent reduction of invasiveness of HES cells. This effect of simvastatin was abrogated by GGPP but not by FPP. Simvastatin also reduced the mRNA levels of MMP2, MMP3, and CD44, but increased TIMP2 mRNA; all these effects of simvastatin were partly or entirely reversed in the presence of GGPP. The present findings provide a novel mechanism of action of simvastatin on endometrial stroma that may explain reduction of endometriosis in animal models of this disease. Furthermore, the presently described effects of simvastatin are likely mediated, at least in part, by inhibition of geranylgeranylation.
最近我们报道称，他汀类药物是调节甲羟戊酸途径关键酶（3-羟-3-甲基戊二酰基辅酶 A 还原酶，HMGCR）的竞争性抑制剂，可降低人子宫内膜基质（HES）细胞的增殖。此外，我们发现辛伐他汀治疗可减少子宫内膜异位症裸鼠模型中子宫内膜植入物的数量和大小。本研究旨在探讨辛伐他汀对 HES 细胞侵袭性的影响，以及对与侵袭性相关的选定基因表达的影响：基质金属蛋白酶 2（MMP2）、基质金属蛋白酶 3（MMP3）、基质金属蛋白酶组织抑制剂 2（TIMP2）和 CD44。由于他汀类药物诱导的 HMGCR 抑制会减少异戊烯基化焦磷酸香叶基（GGPP）和法呢基焦磷酸（FPP）的底物生成，因此还评估了 GGPP 和 FPP 的作用。辛伐他汀诱导 HES 细胞侵袭性呈浓度依赖性降低。这种辛伐他汀的作用被 GGPP 但不是 FPP 所阻断。辛伐他汀还降低了 MMP2、MMP3 和 CD44 的 mRNA 水平，但增加了 TIMP2 mRNA；所有这些辛伐他汀的作用在 GGPP 存在下部分或完全逆转。本研究结果为辛伐他汀对子宫内膜基质的作用提供了一种新的机制，可能解释了该疾病动物模型中子宫内膜异位症的减少。此外，目前描述的辛伐他汀的作用可能至少部分通过抑制 geranylgeranylation 介导。
