Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia

Nakashima, Akitoshi; Saito, Tomoko; Tsuda, S.; Aoki, Aiko; Kawaguchi, Mihoko; Furuta, Atsushi; Yasuda, Ippei; Yoneda, Satoshi; Yamaki-Ushijima, Akemi; Cheng, Shi-Bin; Sharma, Surendra; Saito, Shigeru

doi:10.3390/ijms22052432

Cited by 19 publications

(11 citation statements)

References 82 publications

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“…15 Current studies suggest that the pathogenesis of PE may be related to decidual macrophage dysfunction, 16 placental angiogenesis disorder, 17 placental aging, 18,19 protein aggregation, and defective placental aggregation phagocytosis. 20 At the molecular level, the microRNA spectrum of blood exosomes has been used to evaluate the pathophysiology of preeclampsia and predict the disease, 21 and there are more and more studies at gene level. [22][23][24][25] Zhang and Horvath 26 conducted the first WGCNA analysis in 2005 and then published WGCNA R software package in R based on theory of the research method in 2008.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Yu¹,

Zhao²,

Sun³

et al. 2022

IJGM

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Objective Preeclampsia (PE) is a pregnancy-specific multisystem disease as well as an important cause of maternal and perinatal death. This study aimed to analyze the placental transcriptional data and clinical information of PE patients available in the published database and predict the target genes for prevention of PE. Methods The clinical information and corresponding RNA data of PE patients were downloaded from the GEO database. Cluster analysis was performed to examine the correlation between different genotyping genes and clinical manifestations. Then, bioinformatic approaches including GO, KEGG, WGCNA, and GSEA were employed to functionally characterize candidate target genes involved in pathogenesis of PE. Results Two PE datasets GSE60438 and GSE75010 were obtained and combined, thereby providing the data of 205 samples in total (100 non-PE and 105 PE samples). After eliminating the batch effect, we grouped and analyzed the integrated data, and further performed GSEA analysis. It was found that the genes in group 1 and group 2 were different from those in normal samples. Moreover, WGCNA analysis revealed that genes in group 1 were up-regulated in turquoise module, including SASH1 , PIK3CB and FLT-1 , while genes in group 2 were up-regulated in the blue and brown modules. We further conducted GO and KEGG pathway enrichment analyses and found that the differential genes in turquoise module were mainly involved in biological processes such as small molecular catabolic process, while being highly enriched in pathways, including MAPK signaling pathway and Rap1 signaling pathway. Conclusion FLT-1 was conventionally used to predict PE risk, and sFLT-1 could also be used as an indicator to evaluate PE treatment effect. As a candidate biomarker for predicting PE, SASH1 may participate in proliferation, migration, invasion and epithelial mesenchymal transformation of human trophoblast cells by regulating MAPK pathway and Rap1 signaling pathway, thus affecting the progression of PE. The mechanism allowing PIK3CB to regulate PE development was not clear, while the gene could be another candidate biomarker for PE risk prediction. This is an exploratory study and our findings were still required verification in further studies.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Yu¹,

Zhao²,

Sun³

et al. 2022

IJGM

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“…Autophagy is an evolutionarily conserved cellular process that degrades a bulk of damaged organelles, long-lived proteins, protein aggregates and pathogens through a lysosomal degradation pathway (Huber and Teis, 2016). It includes three distinct pathways, namely macroautophagy, microautophagy and chaperone-mediated autophagy with macroautophagy (or autophagy for short) most widely studied (Oku and Sakai, 2018;Nakashima et al, 2019b;Nakashima et al, 2021). Autophagy including mitophagy can be activated by a variety of stimuli, such as starvation, hypoxia, protein aggregation and infection, and involves a series of dynamic formation of organelles (Ryter et al, 2013).…”

Section: Autophagy and Inflammation In Pe Impaired Autophagy Linked To Pementioning

confidence: 99%

Etiological Value of Sterile Inflammation in Preeclampsia: Is It a Non-Infectious Pregnancy Complication?

Banerjee

Huang

Wang

et al. 2021

Front. Cell. Infect. Microbiol.

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Understanding of sterile inflammation and its associated biological triggers and diseases is still at the elementary stage. This becomes more warranted in cases where infections are not associated with the pathology. Detrimental effects of bacterial and viral infections on the immune responses at the maternal-fetal interface as well as pregnancy outcomes have been well documented. However, an infection-induced etiology is not thought to be a major contributing component to severe pregnancy complications such as preeclampsia (PE) and gestational diabetes. How is then an inflammatory signal thought to be associated with these pregnancy complications? It is not clear what type of inflammation is involved in the onset of PE-like features. We opine that sterile inflammation regulated by the inflammasome-gasdermins-caspase-1 axis is a contributory factor to the onset of PE. We hypothesize that increased production and release of damage-associated molecular patterns (DAMPs) or Alarmins such as high-mobility group box1 (HMGB1), cell-free fetal DNA, uric acid, the NOD-like receptor pyrin-containing receptor 3 (NLRP3) inflammasome, IL-1β and IL-18 occur in the PE placenta. Some of these molecules have already been observed in the placenta from women with PE. Mechanistically, emerging evidence has demonstrated that excessive placental endoplasmic reticulum (ER) stress, impaired autophagy and gasdermine D (GSDMD)-mediated intrinsic pyroptosis are key events that contribute to systemic sterile inflammation in patients with PE, especially early-onset PE (e-PE). In this review, we highlight the advances on the roles of sterile inflammation and inflammatory signaling cascades involving ER stress, autophagy deficiency and pyroptosis in PE pathophysiology. Deciphering the mechanisms underlying these inflammatory pathways may provide potential diagnostic biomarkers and facilitate the development of therapeutic strategies to treat this devastating disease.

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“…The protein degradation is achieved either by the autophagy-lysosomal system for long-lived proteins or by the ubiquitin-proteasome system for short-lived proteins (Nakashima et al, 2019a,b). Autophagy may occur both as macroautophagy, a non-selective degradation process where autophagosomes transport internal contents to lysosomes, and as microautophagy, a selective process targeting mitochondria (mitophagy), endoplasmic reticulum (ER-phagy), protein aggregates (aggrephagy), chromatins (chromatophagy), iron-bound ferritin (ferritinophagy), and pathogens (xenophagy) (Nakashima et al, 2019b(Nakashima et al, , 2021.…”

Section: Role Of Endoplasmic Reticulum In Inappropriate Cell Deathmentioning

confidence: 99%

“…This is attributed to the downregulation of transcriptional factor EB (TFEB), which is also retained by the hyperactivation of mTOR in preeclamptic placenta. In preeclampsia, aggrephagy is reduced or inhibited, resulting in more accumulation of protein aggregates (Nakashima et al, 2021).…”

Section: Role Of Endoplasmic Reticulum In Inappropriate Cell Deathmentioning

confidence: 99%

Preeclampsia: From Cellular Wellness to Inappropriate Cell Death, and the Roles of Nutrition

Lokeswara

Hiksas

Irwinda

et al. 2021

Front. Cell Dev. Biol.

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Preeclampsia is one of the most common obstetrical complications worldwide. The pathomechanism of this disease begins with abnormal placentation in early pregnancy, which is associated with inappropriate decidualization, vasculogenesis, angiogenesis, and spiral artery remodeling, leading to endothelial dysfunction. In these processes, appropriate cellular deaths have been proposed to play a pivotal role, including apoptosis and autophagy. The proper functioning of these physiological cell deaths for placentation depends on the wellbeing of the trophoblasts, affected by the structural and functional integrity of each cellular component including the cell membrane, mitochondria, endoplasmic reticulum, genetics, and epigenetics. This cellular wellness, which includes optimal cellular integrity and function, is heavily influenced by nutritional adequacy. In contrast, nutritional deficiencies may result in the alteration of plasma membrane, mitochondrial dysfunction, endoplasmic reticulum stress, and changes in gene expression, DNA methylation, and miRNA expression, as well as weakened defense against environmental contaminants, hence inducing a series of inappropriate cellular deaths such as abnormal apoptosis and necrosis, and autophagy dysfunction and resulting in abnormal trophoblast invasion. Despite their inherent connection, the currently available studies examined the functions of each organelle, the cellular death mechanisms and the nutrition involved, both physiologically in the placenta and in preeclampsia, separately. Therefore, this review aims to comprehensively discuss the relationship between each organelle in maintaining the physiological cell death mechanisms and the nutrition involved, and the interconnection between the disruptions in the cellular organelles and inappropriate cell death mechanisms, resulting in poor trophoblast invasion and differentiation, as seen in preeclampsia.

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Aggrephagy Deficiency in the Placenta: A New Pathogenesis of Preeclampsia

Cited by 19 publications

References 82 publications

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Gene Expression Network Analysis Identifies Potential Targets for Prevention of Preeclampsia

Etiological Value of Sterile Inflammation in Preeclampsia: Is It a Non-Infectious Pregnancy Complication?

Preeclampsia: From Cellular Wellness to Inappropriate Cell Death, and the Roles of Nutrition

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