Abstract
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.
Highlights
The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world (Wild et al, 2004; Shaw et al, 2010)
The intermediary metabolite in the conversion of mevalonate to the dolichol phosphate needed for subsequent protein glycosylation is farnesyl pyrophosphate; we investigated whether supplementation of placental explants with farnesyl pyrophosphate could prevent statin-mediated disruption of insulin-like growth factor 1 receptor (IGF1R) cell surface expression and, in turn, insulin-like growth factors (IGF)-induced proliferation
Inhibition of Hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase by statins (Stancu and Sima, 2001) results in depletion of mevalonate, and downstream of this, a reduction in the supply of dolichol phosphate needed for N-glycosylation (Carroll et al, 1992); given these effects on cellular metabolism, we hypothesized that our previous finding of reduced trophoblast proliferation in statin-exposed placental explants (Forbes et al, 2008a) was caused by a reduction in IGF1R
Summary
The rapid rise in obesity, metabolic syndrome and type 2 diabetes is one of the major healthcare problems of the Western world (Wild et al, 2004; Shaw et al, 2010). Studies in rodents suggest that administration of statins may have beneficial effects in pregnancy complications, such as pre-eclampsia, that are associated with altered vascular function (Fox et al, 2011; Kumasawa et al, 2011; Bauer et al, 2013). These findings have led to a surge in the number of studies investigating the use of statins in human pregnancy and two randomized control trials are underway (ISRCTN, 2009; Costantine and Cleary, 2013).
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