AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications

Abstract

Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O-methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation.

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

“…Several lines of evidence advocate the use of ER stressors as potential drugs for the treatment of both B-ALL and T-ALL. Earlier studies focused on how the AMP-activated kinase (AMPK) activator 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR [144]) in combination with either methotrexate or 2-deoxy-D-glucose (2-DG, a sugar analog that inhibits both glycolysis and N-linked glycosylation [145]), induced a prolonged ER stress in B-ALL cells, thereby leading to proapoptotic UPR via IRE1α, GRP78, phosphorylated eIF2α, and CHOP [146]. Similar results were reported with the AMPK activator metformin that led to UPR-mediated apoptosis via upregulation of IRE1α and CHOP [138].…”

The potential therapeutic effects of curcumin on pregnancy complications: Novel insights into reproductive medicine

“…Studies of peripheral macrophages show that activation of the JAK2/STAT3 signaling pathway can induce the expression of HMGB1, which promotes the release of cytokines such as TNF-α and IL-6, thus induces the inflammatory reaction. 84 It was found that curcumin supplementation suppresses the phosphorylation levels of the JAK2 in IUGR rats. 57 Furthermore, curcumin can attenuate hepatic oxidative stress by activating the NRF2 pathway.…”

“…84 In a stress state, ATP consumption causes AMPK activation that leads to increased concentration of cellular ATP. 84 AMPK activation has been found to alleviate maternal diabetic disease and consequently normalize fetal growth. 84,99,105 Of note, AMPK activation by curcumin was found to alleviate GD, which is associated with decreased expression of HDAC4 (histone deacetylases-4) and glucose-6-phosphatase (G6Pase).…”

“…84 AMPK activation has been found to alleviate maternal diabetic disease and consequently normalize fetal growth. 84,99,105 Of note, AMPK activation by curcumin was found to alleviate GD, which is associated with decreased expression of HDAC4 (histone deacetylases-4) and glucose-6-phosphatase (G6Pase). 105 HDAC4 modulates endocrine function and glucose homeostasis in the various tissues.…”

Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice

“…Studies have documented the role of FA in suppressing endothelial oxidative stress and placental inflammatory response, which in turn alleviates the disease pathology [15,16]. Moreover, AMPK activation is not only necessary for the placental differentiation and growth but also regulating the inflammatory response in the placenta [45]. Intriguingly, both antiviral and anti-inflammatory effects of FA may play a role in limiting ZIKV transmission through maternal-fetal interface.…”