Secretion of heat shock -60, -70 kD protein, IL-1β and TNFα levels in serum of a term normal pregnancy and patients with pre-eclampsia development.
Álvarez-Cabrera María C,Barrientos-Galeana Edgar,Barrera-García Asyadette,Osorio-Caballero Mauricio,Acevedo Jesús F,Flores-Herrera Oscar,Díaz Néstor F,Molina-Hernández Anayansí,García-López Guadalupe,Flores-Herrera Héctor
Journal of cellular and molecular medicine
The extracellular heat shock proteins (eHsp) family act as molecular chaperones regulating folding, transporting protein and are associated with immune modulation in different physiological and pathological processes. They have been localized in different gestational tissues and their concentration in amniotic fluid and serum has been determined. In the present study, we proposed to determine the concentration of eHsp-60, -70, IL-1β and TNFα in the serum of pregnant patients with 34 weeks of gestation with and without clinical evidences of preeclampsia (PE). Our results indicate significant increase of these markers in patients with PE with respect to healthy pregnant patients without active labor. Finally, the concentration of eHsp-60 and -70 correlated positively with the hepatic dysfunction markers uric acid, lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) glutamic pyruvic transaminase (GPT), and inflammatory IL-1β and TNFα response. In conclusion, our results demonstrate a strong associated between Hsp and marker of hepatic dysfunction.
10.1111/jcmm.13824
Serum heat shock protein 70 levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in women with preeclampsia.
Molvarec Attila,Szarka András,Walentin Szilvia,Beko Gabriella,Karádi István,Prohászka Zoltán,Rigó János
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:We have previously reported that serum levels of 70 kDa heat shock protein (Hsp70, HSPA1A) are increased and reflect systemic inflammation, oxidative stress and hepatocellular injury in preeclampsia. The purpose of this study was to determine whether increased serum Hsp70 concentrations in women with preeclampsia are related to circulating levels of cytokines, chemokines, adhesion molecules and angiogenic factors, the key players in the pathogenesis of the disease. METHODS:Sixty preeclamptic patients and 60 normotensive, healthy pregnant women were involved in this case-control study. Levels of Hsp70 (HSPA1A) and transforming growth factor (TGF)-beta1 in maternal sera were assessed by ELISA. Serum levels of interleukin (IL)-1 beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interferon-gamma-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were determined by multiplex suspension array. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were measured by electrochemiluminescence immunoassay. For statistical analyses, the Mann-Whitney U-test, the Fisher exact and Pearson chi-square tests, the Spearman rank order correlation, multiple linear regression and logistic regression were applied. RESULTS:Serum levels of Hsp70 were significantly higher in preeclamptic patients than in healthy pregnant women. Additionally, most of the measured inflammatory variables differed significantly between the two study groups except for serum IL-1 beta and TGF-beta1 levels and IL-18/IL-12p70 and IL-12p70/IL-12p40 ratios, indicating a bias toward a pro-inflammatory status in preeclampsia. Preeclamptic patients had significantly higher sFlt-1 levels and sFlt-1/PlGF ratio and significantly lower PlGF concentrations as compared to healthy pregnant women. In the preeclamptic group, serum Hsp70 concentrations showed significant correlations with serum levels of IL-12p40 (R=0.59, p<0.001), MCP-1 (R=0.43, p<0.001), ICAM-1 (R=0.39, p=0.0020) and VCAM-1 (R=0.46, p<0.001). Furthermore, elevated serum Hsp70 level and sFlt-1/PlGF ratio had a synergistic (joint) effect in the risk of preeclampsia, as shown by the substantially higher odds ratios of their combination than of either alone. CONCLUSIONS:Increased serum Hsp70 concentrations in women with preeclampsia were associated with pro-inflammatory changes in circulating cytokine profile, suggesting that circulating Hsp70 might contribute to the development of the excessive systemic inflammatory response characteristic of the maternal syndrome of the disease.
10.1016/j.cca.2011.06.042
High levels of heat shock protein 70 are associated with pro-inflammatory cytokines and may differentiate early- from late-onset preeclampsia.
Peraçoli Jose C,Bannwart-Castro Camila F,Romao Mariana,Weel Ingrid C,Ribeiro Vanessa R,Borges Vera T M,Rudge Marilza V,Witkin Steven S,Peraçoli Maria T
Journal of reproductive immunology
Preeclampsia (PE), a specific syndrome of pregnancy, can be classified into early and late onset, depending on whether clinical manifestations occur before or after 34 weeks' gestation. We determined whether plasma concentrations of Hsp60 and Hsp70 were related to circulating cytokine levels, as well as kidney and liver functions, in early- and late-onset PE. Two hundred and thirty-seven preeclamptic women (95 with early- and 142 with late-onset PE) were evaluated. Plasma levels of Hsp60, Hsp70, and their specific antibodies, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-10, IL-12, and soluble TNF-α-receptor I (sTNFRI) concentrations, were determined by enzyme-linked immunosorbent assay (ELISA). Concentrations of Hsp70, TNF-α, IL-1β, IL-12, and sTNFRI were significantly elevated in patients with early-onset PE compared with women with late-onset PE; IL-10 levels were significantly lower in the early-onset PE group. Concentrations of urea, uric acid, proteinuria, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were also significantly higher in early-onset PE. The percentage of infants with intrauterine growth restriction was also significantly higher in women with early-onset PE. There were positive correlations between Hsp70 levels and TNF-α, TNFRI, IL-1β, IL-12, GOT, GPT, LDH, and uric acid concentrations in early-onset PE group. Thus, early-onset PE was associated with greater maternal and fetal impairment. There are differences in pathophysiology between early- and late-onset PE, highlighting by the difference in Hsp70 levels.
10.1016/j.jri.2013.08.003
HSP70-mediated control of endothelial cell apoptosis during pre-eclampsia.
Padmini Ekambaram,Lavanya Srinivasan
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE:Pre-eclampsia is a hypertensive disorder characterized by maternal vascular endothelial dysfunction. It is likely that this enhanced rate of endothelial cell stress is associated with the pre- and post-partum complications of both mother and fetus. Deciphering the expression pattern of factors involved in altering placental endothelial cell viability in pre-eclampsia aids in identifying components that may protect the fetus from the consequences of placental dysfunction and oxidative stress. STUDY DESIGN:Expression of thioredoxin (Trx), an antioxidant protein; heat shock protein (HSP) 70, a cytoprotective protein; heat shock factor (HSF)1, a transcriptional factor of HSPs; and apoptosis signal-regulating kinase 1 (ASK1), a pro-apoptotic protein, was elucidated in endothelial cells from human term placentas of normotensive and pre-eclamptic subjects (n=35). RESULTS:A significant increase in HSP70 (p<0.05), HSF1 (p<0.05), Trx (p<0.05) and an insignificant increase in ASK1 were noted in pre-eclamptic endothelial cells. CONCLUSION:This analysis supports the role of HSP70 expression in promoting cell survival by regulating ASK expression in pre-eclampsia.
10.1016/j.ejogrb.2011.01.026
Mechanism of JNK signal regulation by placental HSP70 and HSP90 in endothelial cell during preeclampsia.
Padmini Ekambaram,Venkatraman Uthra,Srinivasan Lavanya
Toxicology mechanisms and methods
CONTEXT:Preeclampsia is a placenta related disorder of during pregnancy resulting in pre- and post-partum complications of the both mother and fetus. It is associated with improper trophoblast invasion and maternal endothelial cell dysfunction leading to a placental dysregulation resulting in premature delivery. OBJECTIVE:Aim of the present study is to elucidate of the protective role of chaperones (HSP70 and 90) in preeclampsia and to test whether it is associated with oxidative stress level in placental tissue. MATERIALS AND METHODS:Endothelial cell from normotensive and preeclamptic placenta were analyzed for variation in viability and expression of signaling molecules. RESULTS:A significant decrease in viability of endothelial cell (p < 0.05) was noted in preeclamptic samples when compared to normotensive samples. The results indicate that there were increases in HSP70 and HSP90 (p <0.01), HSF1 (p <0.01), NF-κB (p <0.05), JNK1 (p <0.05), JNK2 (p> 0.05) and Bcl2 (p <0.05). DISCUSSION:The significant change in the viability of endothelial cell has not predominantly affected the live fetal delivery during preeclampsia. This is governed by alterations in expression of nuclear transcription factors like HSF1, NF-κB and signaling molecules like JNK1/2 and Bcl2 in preeclamptic endothelial cell. CONCLUSION:This HSP mediated signal changes may contribute to live fetal delivery in spite of existing endothelial cell complication during preeclampsia.
10.3109/15376516.2012.673091
Higher expression of HSP70 and LOX-1 in the placental tissues of pre-eclampsia pregnancies.
Sheikhi Abdolkarim,Razdar Sara,Rahmanpour Haleh,Mousavinasab Nouraddin,Ganji Hossein Barzegar,Jafarzadeh Abdollah
Clinical and experimental hypertension (New York, N.Y. : 1993)
BACKGROUND:Pre-eclampsia, a hypertensive disorder of pregnancy is the main cause of fetal and maternal morbidity and mortality. Growing evidences suggest that placental oxidative stress involves in the pathogenesis of pre-eclampsia. The HSP70 is a novel marker of oxidative stress which binds with high avidity to LOX-1. The aim of this study was to evaluate the co-expression of HSP70 and LOX-1 in the placental tissues of normotensive and pre-eclamptic pregnancies. MATERIALS AND METHODS:The placental tissues were collected from 35 healthy women with normal pregnancies and 33 women with pre-eclampsia disorder. Expression of HSP70 and LOX-1 on the placental tissues was examined by using immunohistochemistry technique. The intensity of the molecules' expression was determined by semi-quantitative scoring. RESULTS:The 34.3% and 37.1% of the healthy women did not express the HSP70 and LOX-1 on their placenta, respectively. All pre-eclamptic patients expressed HSP70 and LOX-1 with various scores. Indeed, the majority of the pre-eclamptic subjects had ≥3+ scores of the expression of HSP70 and LOX-1 on their placenta (60.6% and 66.7%, respectively). The percentage of the ≥3+ scores of the expression of HSP70 and LOX-1 was significantly higher in patients than those in healthy women (p<0.0001 for both). Similarly, the majority of the pre-eclamptic subjects had ≥3+ scores of the co-expression of HSP70 and LOX-1 molecules (57.6%) which was significantly higher in patients than those in control group (p=0.0001). CONCLUSIONS:These results showed higher expression of HSP70 and LOX-1 in the placental tissues of pre-eclampsia patients which represent the possible contribution of these molecules in the disease pathogenesis. Further studies need to clarify their role in the pathogenesis of preeclampsia disorder.
10.3109/10641963.2014.913607
Induction of systemic inflammation by hyaluronan and hsp70 in women with pre-eclampsia.
Romão-Veiga Mariana,Matias Mariana Leticia,Ribeiro Vanessa Rocha,Nunes Priscila Rezeck,M Borges Vera Therezinha,Peraçoli José Carlos,Peraçoli Maria Terezinha S
Cytokine
Pre-eclampsia (PE) is a human pregnancy syndrome with abnormal activation of the innate immune response. The study evaluated the involvement of molecular structures called damage-associated molecular patterns (DAMPs), such as hyaluronan (HA) and heat shock proteins (Hsp) on NLRP1 and NLRP3 inflammasomes activation in peripheral blood monocytes. Twenty pre-eclamptic women, 20 normotensive pregnant women (NT) and 20 non-pregnant women (NP) were studied. Enzyme immunoassay was employed for the determination of HA, Hsp70 and High mobility group Box 1 (HMGB1) in plasma, as well as for the detection of Interleukin-1β (IL-1β), IL-18 and tumor necrosis factor alpha (TNF-α) in the supernatant of monocytes cultured with or without HA and Hsp70. The inflammasomes induction was evaluated by the quantification of mRNA for NLRP1, NLRP3, caspase-1, IL-1β, IL-18, HMGB1 and TNF-α by qPCR in monocyte culture. The results showed significantly higher plasma levels of HA, Hsp70 and HMGB1 in pre-eclamptic women than in NT and NP women. Monocytes from women with PE showed endogenous activation of NLRP1 and NLRP3 inflammasomes, and expressed high amounts of IL-1β, IL-18, HMGB1 and TNF-α. The stimulation of monocytes with HA increased the gene expression of NLRP1, NLRP3, caspase-1, TNF-α, IL-1β, HMGB1 and IL-18 and the production of IL-1β in pre-eclamptic women. Monocytes cultured with Hsp70 produced elevated levels of IL-1β and TNF-α through a mechanism independent of inflammasomes activation. These results suggest the participation of these DAMPs in the systemic inflammatory response that is characteristic of PE.
10.1016/j.cyto.2018.02.007
[Expression and significance of heat shock protein 70 in maternal serum, umbilical cord blood and placenta of patients with hypertensive disorders complicating pregnancy].
Zhu Jinming,Li Min,Li Lei
Zhonghua fu chan ke za zhi
OBJECTIVE:To investigate the expression of heat shock protein 70 (HSP70) in maternal serum, umbilical cord blood and placenta of patients with hypertensive disorders complicating pregnancy (HDCP) and to discuss its role in the pathogenesis of HDCP. METHODS:Totally 90 patients with HDCP were recruited as HDCP group, and were devided into three subgroups, including gestational hypertension group (30 cases), mild preeclampsia group (30 cases) and severe preeclampsia group (30 cases). A totally of 30 cases of healthy pregnant women were defined as the control group. All of them were admitted to Xuzhou Maternity and Child Health Care Hospital from August 2011 to December 2012. ELISA was used to detect the expression of HSP70 in maternal serum and umbilical cord blood. Immunohistochemistry streptavidin peroxidase (SP) was used to detect the protein in placenta, and semi-quantitative reverse transcription (RT)- PCR was used to detect the expression of HSP70 mRNA. RESULTS:(1) The levels of HSP70 in maternal serum and cord blood of mild preeclampsia group were (2.61 ± 0.98) and (0.78 ± 0.27) µg/L, respectively; and were (3.10 ± 1.18) and (0.96 ± 0.28) µg/L in severe preeclampsia group. The levels of HSP70 in mild and severe preeclampsia groups were significantly higher than those in the control group [(1.88 ± 0.79) and (0.61 ± 0.15) µg/L, respectively] and gestational hypertension group [(2.13 ± 0.71) and (0.64 ± 0.18) µg/L, respectively; P < 0.05]. The level of HSP70 in severe preeclampsia group was significantly higher than that in mild preeclampsia group (P < 0.05). And the level of HSP70 in gestational hypertension group was higher than that in the control group, but there was no statistical difference (P > 0.05). (2) The positive rate of placental HSP70 in gestational hypertension group, mild and severe preeclampsia group [83% (25/30), 90% (27/30) and 100% (30/30)], respectively were significantly higher than those in the control group (43%, 13/30; P < 0.05). The positive rate of placental HSP70 in severe preeclampsia group was significantly higher than that in gestational hypertension group and mild preeclampsia group (P < 0.05). (3) The expression of placental HSP70 mRNA in gestational hypertension group, mild and severe preeclampsia group (0.82 ± 0.27, 0.92 ± 0.26 and 1.36 ± 0.29, respectively) were significantly higher than that in the control group (0.45 ± 0.18), with statistically significant differences (P < 0.05). The expression of placental HSP70 mRNA in severe preeclampsia group was significantly higher than that in gestational hypertension group and mild preeclampsia group (P < 0.05). CONCLUSION:The expression of HSP70 increased significantly in maternal serum, umbilical cord blood and placenta of patients with HDCP, and it had positive correlation with the severity of the disease, indicating that HSP70 may play a role in the pathogenesis of HDCP.
Circulating heat shock protein mRNA profile in gestational hypertension, pre-eclampsia & foetal growth restriction.
Hromadnikova Ilona,Dvorakova Lenka,Kotlabova Katerina,Kestlerova Andrea,Hympanova Lucie,Novotna Veronika,Doucha Jindrich,Krofta Ladislav
The Indian journal of medical research
BACKGROUND & OBJECTIVES:Heat shock proteins (Hsp) are ubiquitously distributed phylogenetically conserved molecules that regulate cellular homeostasis and maintain the integrity and function of cellular proteins. Increased levels of Hsp in maternal circulation have been shown to be associated with increased risk of pregnancy related complications. The objective of this study was to explore extracellular Hsp mRNA levels in maternal circulation and quantified Hsp27, Hsp60, Hsp70, Hsp90 and Hsp70 binding protein 1 (HspBP1) mRNAs in maternal plasma samples using real-time reverse-transcriptase polymerase chain reaction. METHODS:Pregnancies with gestational hypertension (GH) (n = 33), pre-eclampsia (PE) with or without foetal growth restriction (FGR) (n = 78) and FGR (n = 25) were involved in the study. Hsp gene expression was analysed in relation to the severity of the disease with respect to the degree of clinical signs, requirements for the delivery and Doppler ultrasound parameters. RESULTS:Upregulation of Hsp70 was observed in patients with mild and severe PE (P = 0.004 and P = 0.005, respectively) and in pregnancies complicated with PE delivering before and after 34 wk of gestation regardless of the degree of clinical signs (P = 0.015 and P = 0.009, respectively). No difference in the expression of other Hsp genes among the studied groups was observed. No association between Hsp gene expression and Doppler ultrasonography parameters was found. INTERPRETATION & CONCLUSIONS:These data support that maternal circulation can reflect both maternal and foetal pathologic conditions. Hsp70 represents the sole plasmatic marker, and increased Hsp70 mRNA levels reflect maternal and placental stress response to pregnancy-related complications such as GH and PE, irrespective of the severity of the disease.
10.4103/0971-5916.195037