AMPK Hyper-Activation Alters Fatty Acids Metabolism and Impairs Invasiveness of Trophoblasts in Preeclampsia

Abstract

Background/Aims: Preeclampsia (PE) has long been assumed to be an ischemic disease of the placenta, although there is limited evidence as to how the ischemia impacts on the placenta. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism and plays an important role in a variety of ischemic diseases by enhancing energy production. The present study investigated placental metabolism in PE, and the role of AMPK in regulating trophoblast function. Methods: placentas from normal and PE complicated pregnancies were subjected to GC-MS to identify fatty acids (FA) metabolic fingerprints, and total FA oxidation was assessed by malondialdehyde (MDA) measurement. The AMPK-ACC signaling pathway was assessed by q-PCR and Western Blotting. HTR8/SVneo trophoblast cultures were exposed to different oxygenation conditions to establish an in vitro PE cell model; further analysis by GC-MS for metabolite profiling was then undertaken. Trophoblasts invasion was assessed by a matrigel transwell assay in the presence/absence of AMPK expression and after manipulations of AMPK activity, and then further validated by human villi outgrowth experiments. Results: AMPK phosphorylation and MDA production were significantly elevated in placentas from pregnancies complicated by PE. Metabolism of cis double bond FA was inhibited while trans double bond FA metabolism was promoted in PE placentas. HTR8/SVneo cell culture conditions of persistent low oxygenation mimicked the hyper-activation of AMPK and enhanced the FA oxidation that was observed in PE. AMPK activation impaired trophoblast invasion, while AMPK inhibition promoted trophoblast invasion. Conclusion: PE complicated placentas are associated with AMPK hyper-activation and consequent alterations in FA oxidation, which inhibit trophoblast invasion.

Hypoxia-induced Downregulation of SRC-3 Suppresses Trophoblastic Invasion and Migration Through Inhibition of the AKT/mTOR Pathway: Implications for the Pathogenesis of Preeclampsia

“…In early gestation, trophoblast cells have to be resistant to a low oxygen intrauterine environment 44–46 . However, in placentas of pregnancies complicated by preeclampsia, low oxygen triggers a hypoxic response, which leads to an elevation of HIF-1α, a consequent reduction in trophoblast invasion, and placental hypoperfusion.…”

The Effects of Early-Onset Pre-Eclampsia on Placental Creatine Metabolism in the Third Trimester

“…The current study did find a 2-fold increase mRNA expression of the creatine transporter SLC6A8 in PE placentae compared to controls. A potential mechanistic pathway for increased creatine transporter expression and activity in the placenta is via AMP-activated protein kinase (AMPK), a key regulator of cellular energy metabolism that has been implicated in the pathophysiology of PE [29]. In cardiomyocytes, activation of AMPK pathways has been shown to up-regulate creatine transporter expression and activity, ultimately increasing cellular creatine up-take [30].…”

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

“…As forementioned, LKB1 is the upstream inducer of AMPK. Hyperactivation of AMPK is found in the placentas from preeclamptic patients, which is associated with disturbed fatty acid metabolome and impaired trophoblast invasion 96 . In the present study, we report an upregulation of Pon2 and Pla2 in the placentas of citrulline-treated DSSR.…”