Sirtuins: Subtle Regulators Involved in Convoluted Mechanisms of Pregnancy

Abstract

Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated in starving cells in response to stringent conditions, in which levels of NAD+ are increased. Each member of the Sirtuin family is prominently involved in the regulation of myriad fundamental biological processes including inflammation, proliferation, cell survival, DNA repair and metabolism. Sirtuins can also interact with various signaling pathways and factors such as hypoxia-inducible factors (HIFs), mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and the Notch pathway, yet these interactions are demonstrated to be rather complicated. Therefore, deficiency in each member of the Sirtuin family results in severe developmental defects and irregularities both in animals and humans. Currently, a rapidly expanding body of evidence supports that Sirtuins can improve the pregnancy outcome. In fact, each Sirtuin isoform plays distinct yet fundamental roles in controlling folliculogenesis, oocyte meiotic maturation, oocyte aging, trophoblast functions, feto-maternal inflammation and placental angiogenesis and oxidative stress. Consequently, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several pregnancy disorders such as fetal growth retardation, preeclampsia and the HELLP syndrome. Furthermore, Sirtuins also appear to be involved in the regulation of parturition and pregnancy complications caused by maternal obesity and diabetes. In this review, we shall first address Sirtuin regulation and functions including their interactions with the most important signaling pathways involved in pregnancy. Then, we will focus on the pivotal roles of Sirtuins in female reproductive functions, normal pregnancy, parturition and pregnancy complications.