Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

Gerasimova, Elizaveta V.; Fedotov, S.; Kachkin, Daniel V.; Vashukova, Elena S.; Glotov, Andrey S.; Chernoff, Yury O.; Rubel, Aleksandr A.

doi:10.3390/ijms20246183

Cited by 37 publications

(28 citation statements)

References 152 publications

(205 reference statements)

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“…Many proteins, like amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, and ceruloplasmin are misfolded, and the amyloid-like aggregates are found in the placenta, as well as in body fluids. These aggregates appear to induce ER stress, impaired trophoblast invasion, and placental ischemia, which culminates in PE condition [ 169 ].…”

Section: Pathogenesis Of Preeclampsiamentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.

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Section: Pathogenesis Of Preeclampsiamentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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“…The most important amyloid-associated diseases include Alzheimer’s and Parkinson’s diseases, type 2 diabetes, and transmissible spongiform encephalopathies (TSEs), or prion diseases, such as Creutzfeldt-Jakob disease [ 6 ]. Recent data indicate that amyloids are also associated with preeclampsia and some forms of cancer, although this is unclear whether amyloids cause these diseases or arise as a consequence of the disease and serve as biomarkers [ 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Functional Mammalian Amyloids and Amyloid-Like Proteins

Rubel

Fedotov

Grizel

et al. 2020

Life

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Amyloids are highly ordered fibrous cross-β protein aggregates that are notorious primarily because of association with a variety of incurable human and animal diseases (termed amyloidoses), including Alzheimer’s disease (AD), Parkinson’s disease (PD), type 2 diabetes (T2D), and prion diseases. Some amyloid-associated diseases, in particular T2D and AD, are widespread and affect hundreds of millions of people all over the world. However, recently it has become evident that many amyloids, termed “functional amyloids,” are involved in various activities that are beneficial to organisms. Functional amyloids were discovered in diverse taxa, ranging from bacteria to mammals. These amyloids are involved in vital biological functions such as long-term memory, storage of peptide hormones and scaffolding melanin polymerization in animals, substrate attachment, and biofilm formation in bacteria and fungi, etc. Thus, amyloids undoubtedly are playing important roles in biological and pathological processes. This review is focused on functional amyloids in mammals and summarizes approaches used for identifying new potentially amyloidogenic proteins and domains.

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“…Furthermore, A1AT-OE or A1AT administration increases the migration and invasion of human umbilical vein endothelial cells from women with PE [ 19 ]. Conversely, it has been reported that A1AT expression is high in placentas from patients with PE [ 24 ] and that the urinary A1AT concentration is high in women with PE [ 5 , 25 , 26 ]. Our data suggest that A1AT regulates cell motility via ER stress and HTRA1 expression in trophoblast cells, and that dysregulation may be associated with complications of pregnancy, including PE ( Table S1 ).…”

Section: Discussionmentioning

confidence: 99%

Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

Yoshida

Kusama

Fukushima

et al. 2021

IJMS

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Alpha-1 antitrypsin (A1AT) is a glycoprotein that has been shown to protect tissues from proteolytic damage under various inflammatory conditions. Several studies show that A1AT may be associated with pre-eclampsia. However, the role of A1AT expression in placental physiology is not fully understood. In the present study, we aim to characterize the expression and function of placental A1AT. A1AT knockdown is found to reduce the expression of the serine protease HTRA1 in a trophoblast cell line. In addition, A1AT overexpression (A1AT-OE) increases the expression of HTRA1, IL6, CXCL8, and several markers of endoplasmic reticulum (ER) stress. Treatment with tunicamycin or thapsigargin, which induces ER stress, increases HTRA1 expression. Furthermore, immunohistochemistry reveals that HTRA1 is expressed in trophoblasts and the endometrial decidual cells of human placentas. An invasion assay shows that A1AT and HTRA1 stimulate cell invasion, but treatment with the ER stress inhibitors reduces the expression of HTRA1 and ER stress markers and prevents cell invasion in A1AT-OE trophoblasts. These results suggest that endogenous A1AT regulates inflammatory cytokine expression and HTRA1-induced trophoblast invasion via the induction of ER stress. It is concluded that an imbalance in the functional link between A1AT and ER stress at the maternal–fetal interface might cause abnormal placental development.

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Protein Misfolding during Pregnancy: New Approaches to Preeclampsia Diagnostics

Cited by 37 publications

References 152 publications

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Functional Mammalian Amyloids and Amyloid-Like Proteins

Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

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