Increased interaction between heat shock protein 27 and mitogen‐activated protein kinase (p38 and extracellular signal‐regulated kinase) in pre‐eclamptic placentas

Shin, Junga; Jeong, Young-Taek; Jo, Hyun-Cheol; Kang, Mi‐Jin; Chang, In-Suk; Baek, Jong-Chul; Park, Ji Kwon; Lee, Soon-Ae; Lee, Jong-Hak; Choi, Woong; Paik, Woon Ki

doi:10.1111/j.1447-0756.2009.01053.x

Cited by 17 publications

(23 citation statements)

References 22 publications

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“…In keeping with our data, miR-377 expression was found to be up-regulated in fibroblast cell lines under growth arrest, and its expression is reported to be negatively correlated with that of promitogenic signaling molecules (41). Both trophoblast proliferation (1) and ERK expression (42) are altered in placentas from pregnancies complicated by pre-eclampsia; thus, it is tempting to Pre-miR-145 (500 nM) was transfected into first trimester placental explants. 48 h later, total RNA was extracted, and mRNA expression of multiple genes was assessed using PCR pathway arrays.…”

Section: Discussionmentioning

confidence: 49%

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Farrokhnia

Aplin

Westwood

et al. 2014

Journal of Biological Chemistry

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Placental cell growth depends on an adaptable combination of an endogenous developmental program and the exogenous influence of maternal growth factors, both of which may be influenced by microRNA (miR)-dependent effects on gene expression. We have previously shown that global miR suppression in placenta accelerates proliferation and enhances levels of growth factor signaling mediators in cytotrophoblast. This study aimed to identify miRs involved in regulating placental growth. An initial array revealed 58 miR species whose expression differs between first trimester, when cytotrophoblast proliferation is rapid, and term, by which time proliferation has slowed. In silico analysis defined potential growth-regulatory miRs; among these, hsa-miR-145, hsa-miR-377, and hsa-let-7a were predicted to target known placental growth genes and were higher at term than in the first trimester, so they were selected for further analysis. Overexpression of miR-377 and let-7a, but not miR-145, in first trimester placental explants significantly reduced basal cytotrophoblast proliferation and expression of ERK and MYC. PCR arrays, in silico analysis, Western blotting, and 3′-UTR luciferase reporter assays revealed targets of miR-145 within the insulin-like growth factor axis. Analysis of proliferation in placental explants overexpressing miR-145 demonstrated its role as a mediator of insulin-like growth factor-induced trophoblast proliferation. These findings identify miR-377 and let-7a in regulation of endogenous cell growth and miR-145 in the placental response to maternal stimulation and will aid the development of therapeutic strategies for problem pregnancies.

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Section: Discussionmentioning

confidence: 49%

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Farrokhnia

Aplin

Westwood

et al. 2014

Journal of Biological Chemistry

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“…The preeclamptic pregnancy is the most studied among pregnancy-specific complications due to its strong association stress which can result into endothelial dysfunction. Hsp70 and Hsp27 are well-known stress response proteins expressed under various pathological conditions, including trauma, and focal or global ischemia (37). The present study demonstrated that Hsp70 and Hsp27 proteins were increased in preeclamptic women.…”

Section: Discussionsupporting

confidence: 50%

“…Studies have shown that Hsp70 levels in pregnant women are significantly higher than those in healthy pregnant women (18,19). It is also known that placental levels of Hsp27 in normal patients are lower than those in patients with preeclampsia (20).…”

Section: Introductionmentioning

confidence: 99%

Genomic and proteomic investigation of preeclampsia

Şahın

Günel

Benian

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of this study was to use proteomic and transcriptomic approaches to examine differences in protein and gene expression in maternal plasma between normal and preeclamptic pregnancies. Preeclampsia and control groups were compared with respect to the expression of CD34 and CD133 genes by quantitative polymerase chain reaction (qPCR) and heat shock protein (Hsp)27 and 70 by western blotting in blood samples from the pregnant women. Blood samples were obtained at gestational week 12-14 from 65 healthy pregnant women. Fetal DNA was isolated from the maternal blood and CD34 and CD133 were amplified by qPCR. Western blot analysis was used to examine the expression levels of Hsp27 and Hsp70 proteins. The analysis of CD133 by qPCR was unsuccessful in 7 women as the levels of fetal DNA were in the collected maternal blood samples were insufficient. Measurements of CD34 and CD133 were performed in 57 and 50 women, respectively. Preeclampsia developed in 6 (10.5%) of 57 women. qPCR results of 8 healthy pregnant women were used for the calibration of CD34 and CD133 levels, and the results for the remaining women were compared with the calibration values. CD34 expression was decreased in 30 (52.6%) and increased in 27 (47.4%) of 57 women. CD133 expression was decreased in 14 (28%) and increased in 36 (72%) of 50 women. CD34 expression was increased in 2 (33%) and 25 (49%) and decreased in 4 (66%) and 25 (51%) women with and without preeclampsia, respectively (P=0.467). CD133 expression was increased in 4 (66%) and 32 (72%); and decreased in 2 (33%) and 12 (28%) women with and without preeclampsia, respectively (P=0.756). Western blotting showed that the expression of Hsp27 and Hsp70 in the maternal serum of the preeclampsia group was significantly higher than that in the normal pregnancy group. CD34 and CD133 were found to be inadequate for use in the prediction of preeclampsia. However, it is noteworthy that CD133 levels were increased in 66 and 72% of women with and without preeclampsia, respectively. Hsps are expressed under various pathological conditions. These results suggest that conditions of oxidative stress increased the Hsp27 and Hsp70 protein levels.

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“…It encodes for a small protein (17 kDa) and has been reported to be implicated in cell cycle arrest, apoptosis, DNA repair, and the maintenance of genomic stability via the activation of several downstream stress response proteins such as the p38/JNK kinases (Amanullah et al 2003;Bulavin et al 2003;Gupta et al 2006;Hollander et al 1999;Tront et al 2006;Zerbini et al 2004). Interestingly, the stress-responsive p38 MAPK pathway is reported to be robustly activated in PE (Shin et al 2009) and is essential to oxidative stress-mediated placental dysfunction (Cindrova-Davies et al 2007). However, few data are available on the potential function of Gadd45α in the process of placental oxidative stress.…”

Section: Introductionmentioning

confidence: 95%

Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia

Luo

Yao

et al. 2011

Cell Tissue Res

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Preeclampsia (PE) is known to be associated with increased circulating levels of anti-angiogenic factors, such as soluble fms-related tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). However, the way that placental oxidative stress results in the elevation of these two factors remains enigmatic. We have observed the overexpression of growth arrest and DNA damage-inducible 45 alpha (Gadd45α) and excessive activation of p38 mitogen-activated protein kinase (MAPK) in preeclamptic placentas compared with normotensive controls, together with increased levels of sFlt-1 and sEng in maternal sera in patients with PE. Moreover, Gadd45α knockdown or p38 inhibition provides protective effects in hypoxia/reoxygenation (H/R)-exposed human umbilical vein endothelial cells (HUVECs) by suppressing oxidative stress, inhibiting apoptosis, and promoting their potential for in vitro angiogenesis. A regulatory signaling pathway in which H/R intervention causes the induction of Gadd45α leading to p38 activation and ultimately an increase in sFlt-1 and sEng secretion in HUVECs has concurrently been established. Our study opens up a promising new avenue of investigation for increasing the understanding of the origin of sFlt-1 and sEng in PE and provides novel therapeutic targets for pregnancy complications arising from placental endothelial dysfunction.

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Increased interaction between heat shock protein 27 and mitogen‐activated protein kinase (p38 and extracellular signal‐regulated kinase) in pre‐eclamptic placentas

Abstract: The interaction between Hsp27 and MAPK was increased, suggesting that phosphorylation of Hsp27 might be induced by p38 and ERK in placentas from patients with pre-eclampsia.

Cited by 17 publications

References 22 publications

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

MicroRNA Regulation of Mitogenic Signaling Networks in the Human Placenta

Genomic and proteomic investigation of preeclampsia

Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia

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