Premature placental senescence is a hallmark of pregnancy-related disorders such as
intrauterine growth restriction (IUGR) and
preeclampsia (PE), two major cause of maternal and neonatal morbidity and mortality. Oxidative stress and lipid peroxidation are involved in the pathogenesis of PE and IUGR, and may play a role in placental aging. In this study, we investigated whether
4-hydroxy-2-nonenal (HNE), a lipid peroxidation-derived
aldehyde present in preeclamptic placentas, may contribute to premature senescence in placenta-related complications. Placentas from PE-affected women, exhibited several senescence patterns, such as an increased expression of phosphorylated (serine-139)
histone γH2AX, a sensitive marker of double-stranded DNA breaks, the presence of
lipofuscin granules, and an accumulation of high molecular weight cross-linked and
ubiquitinated proteins. PE placentas showed an accumulation of acetylated
proteins consistent with the presence of HNE-adducts on
sirtuin 1 (
SIRT1). Likewise, oxidative stress and senescence markers together with
SIRT1 modification by HNE, were observed in murine placentas from mice treated with
lipopolysaccharide during gestation and used as models of IUGR. The addition of HNE and ONE (4-oxo-2-nonenal), to cultured HTR-8/SVneo human trophoblasts activated the senescence-associated- β-
galactosidase, and generated an accumulation of acetylated
proteins, consistent with a modification of
SIRT1 by HNE. Altogether, these data emphasize the role of HNE and lipid peroxidation-derived
aldehydes in premature placental senescence in PE and IUGR, and more generally in pathological pregnancies.