Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation.
Statins inhibit insulin-like growth factor action in first trimester placenta by altering insulin-like growth factor 1 receptor glycosylation.
复制标题
DOI：
10.1093/molehr/gau093
复制
发表时间：
2015-01
影响因子：
4
通讯作者：
Westwood M
中科院分区：
文献类型：
--
作者：
Forbes K;Shah VK;Siddals K;Gibson JM;Aplin JD;Westwood M
肥胖、代谢综合征和2型糖尿病的快速上升是西方世界的主要医疗保健问题之一。受影响的个体通常使用他汀类药物（3-羟基-3-甲基戊二酰辅酶A [HMG CoA]还原酶抑制剂）治疗，以降低循环胆固醇水平和发生心血管疾病的风险;鉴于这些疾病的人口统计学特征不断变化，此类药物越来越多地用于育龄妇女。我们以前已经表明，胎盘组织暴露于他汀类药物抑制胰岛素样生长因子（IGF）-I和-II的作用，这是滋养层细胞增殖和胎盘发育的关键调节因子。IGF受体IGF 1 R中的N-连接聚糖影响其在细胞表面的呈递。本研究旨在确定已知影响N-糖基化的他汀类药物是否调节胎盘中的IGF 1 R功能。用他汀类药物（普伐他汀或西立伐他汀）或N-糖基化抑制剂（衣霉素、脱氧甘露尻霉素或栗精胺）处理妊娠早期绒毛组织外植体改变了滋养层中的受体分布，并减弱了IGF-I或IGF-II诱导的增殖（Ki 67; P < 0.05，n = 5）。减少菜豆凝集素和植物血凝素结合IGF 1 R免疫沉淀处理的外植体表现出复杂的N-连接聚糖的水平降低。组织外植体与他汀类药物和焦磷酸法呢酯（增加多萜醇中间体的供应）的共孵育，防止了他汀类药物介导的IGF 1 R定位的破坏，并逆转了对IGF介导的滋养层增殖的负面影响。这些数据表明，他汀类药物通过抑制N-连接糖基化和随后胎盘细胞表面成熟IGF 1 R的表达来减弱胎盘中的IGF作用。
The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world. Affected individuals are often treated with statins (3-hydroxy-3-methylglutaryl co-enzyme A [HMG CoA] reductase inhibitors) to reduce circulating cholesterol levels and the risk of developing cardiovascular disease; given the evolving demographic profile of these conditions, such drugs are increasingly prescribed to women of reproductive age. We have previously shown that exposure of placental tissue to statins inhibits the action of insulin-like growth factors (IGF)-I and -II which are key regulators of trophoblast proliferation and placental development. N-linked glycans in the IGF receptor, IGF1R, influence its presentation at the cell surface. This study aimed to determine whether statins, which are known to affect N-glycosylation, modulate IGF1R function in placenta. Treatment of first trimester villous tissue explants with statins (pravastatin or cerivastatin) or inhibitors of N-glycosylation (tunicamycin, deoxymannojirimycin or castanospermine) altered receptor distribution in trophoblast and attenuated proliferation induced by IGF-I or IGF-II (Ki67; P < 0.05, n = 5). Decreased binding of Phaseolus vulgaris lectin and phytohaemagglutinin to IGF1R immunoprecipitated from treated explants demonstrated reduced levels of complex N-linked glycans. Co-incubation of tissue explants with statins and farnesyl pyrophosphate (which increases the supply of dolichol intermediates), prevented statin-mediated disruption of IGF1R localization and reversed the negative effect on IGF-mediated trophoblast proliferation. These data suggest that statins attenuate IGF actions in the placenta by inhibiting N-linked glycosylation and subsequent expression of mature IGF1R at the placental cell surface.
登录
查看更多内容
影响因子：
4.3
作者：
Dricu, A;Kanter, L;Larsson, O
通讯作者：
Larsson, O
影响因子：
0.7
作者：
Aplin, John D.
通讯作者：
Aplin, John D.
影响因子：
2.9
作者：
Godfrey, Laura M.;Erramouspe, John;Cleveland, Kevin W.
通讯作者：
Cleveland, Kevin W.
影响因子：
64.5
作者：
BAKER, J;LIU, JP;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A
影响因子：
2.9
作者：
CARROLL, KK;GUTHRIE, N;RAVI, K
通讯作者：
RAVI, K