Altered Expression of ADAMTSs and HAPLNs in Preeclamptic Placenta.
Preeclampsia (PE) is one of the major causes of perinatal and maternal morbidity and mortality affecting 5%-10% of pregnant women worldwide. PE is a pregnancy-specific complex condition defined by the new onset of hypertension (blood pressure >140/90 mmHg) accompanied by a significant proteinuria (>0.3 g/24 h) emerging after 20 weeks of gestation (1). Severe progression of the disease has been associated with maternal renal damage, liver dysfunction, and eventually seizures and death (2). Although the pathophysiology of PE is unclear, abnormal placentation appears to be a key factor accounting for the development of PE.
Implantation and placentation are crucial processes in the development and maintenance of a successful pregnancy (3). During normal pregnancy, the trophoblast cells that are highly invasive shift to the myometrium and decidua, thereby attacking the muscularis tunica media together with the endothelium of spiral arteries. Trophoblast invasion contributes to the loss of smooth muscle tissues from the uterine spiral arteries' distal part. The uterine artery's terminal branches become vessels that withstand low resistance and increased capacity, thereby facilitating the blood flow required for proper placental development (4, 5). This invasive process is disrupted in PE. In PE, several factors hinder the invasion of trophoblasts into the uterine wall leading to inadequate remodeling of the spiral arteries and consequently poor placental perfusion (6, 7).
Activation of distinct extracellular matrix (ECM) components and/or proteolytic degradation as well as the controlled variation in the cell-ECM and cell-cell interactions are important factors involved in inadequate remodeling of the spiral arteries and abnormal invasion of the trophoblast in PE (8, 9). The definitive molecular mechanisms regulating trophoblast migration/invasiveness during gestation and their relationship with feto-placental development remain largely unknown; however, a number of cytokines, proteinases as well as growth factors appear to be involved in the invasive behavior of trophoblast (3, 10, 11).
A disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) is a family of ECM proteinases comprising 19 secreted proteolytic enzymes that are structurally and functionally related to matrix metalloproteinases (MMPs) (12). Enzymatic activities of these proteases are inhibited by tissue inhibitor of metalloproteinase-3 (TIMP-3) (12). ADAMTSs play a critical role in the remodeling of ECM as well as many other physiological processes, including embryonic development, cell migration, and angiogenesis (13, 14). ADAMTS family members have been implicated in the pathologies of many diseases, including cancer, inflammatory conditions, especially arthritic diseases, and atherosclerosis (14). A limited number of studies have shown the expression pattern of some ADAMTS subtypes in human placenta and their possible implication in gestational trophoblastic diseases (15, 16); however, a more comprehensive study is required to show the expression pattern of all ADAMTS family members in preeclamptic placentas.
The ECM structural substrates, such as versican, aggrecan, and collagen are degraded by the ADAMTS family members (14). On the other hand, hyaluronan, an ECM's basic component, is aided by versican in stabilizing the matrix (17). Circulating hyaluronan concentration has been shown to be elevated in women suffering from PE (18). Hyaluronan and proteoglycan link proteins (HAPLN) are glycoproteins located in the ECM of various tissues, such as brain, cartilage, as well as heart (19). HAPLN genes are responsible for the generation and stabilization of the hyaluronan and proteoglycan aggregates degraded by proteases, including ADAMTS subtypes (20). Therefore, comprehending the ECM elements and factors concerned with the remodeling of ECM in PE is crucial for revealing the new therapeutic targets and treatment methods. Based on this objective, we assessed the expression patterns of ADAMTSs and their potential molecular partners, TIMP-3 and HAPLN gene family members, in both control and preeclamptic placentas.
MATERIALS and METHODS
This study was approved by the local ethical committee. Informed consent was obtained from all participants included in the study. Overall, 10 preeclamptic placentas from women diagnosed with preeclampsia and 10 control placentas from healthy pregnant women were included in the present study. PE pregnant women were selected based on an elevated systolic and diastolic blood pressure (>140/90 mm Hg) that emerged after 20 weeks of gestation, accompanied by proteinuria (300 mg/24 h) that was detected after urine analysis. Preeclamptic pregnant women with infection, chronic hypertension, or any other chronic diseases were excluded from the study. Patients with intrauterine growth restriction were also excluded from the study. To match the gestational ages of PE placentas and control placentas, asymptomatic patients who had spontaneous preterm delivery induced by uterine distension have been included as control. Control women had no chronic and gestational hypertension, proteinuria, infection, and any other chronic diseases during pregnancy. Table 1 shows the demographic and clinical features of control women and women with preeclampsia.
Placental tissue collection
Samples of placental tissue (1 cm x 1 cm x 1 cm) obtained from healthy pregnant women and women with PE immediately after cesarean deliveries were cut out from the maternal side around the umbilical cord in a sterile condition and immediately flash frozen using liquid nitrogen. The flash-frozen placental tissues were stored at -86 [degrees]C until Western blot analysis.
Antibodies for Western blot
Antibodies against TIMP-3, HAPLN subtypes (-1, -2, and -4), and ADAMTS proteases (-4, -8, -10, -12, -13, -14, -16, -18, and -19) were purchased from Santa Cruz Biotechnology. Anti-[beta]-actin, HRP-conjugated goat anti-mouse, and HRP-conjugated goat antirabbit antibodies were obtained from Abcam.
Western blot analysis
The snap frozen placenta was grinded to a fine powder in a chilled mortar in the presence of liquid nitrogen. Immediately after grinding, the placenta powder was lysed on ice in RIPA buffer (Sigma-Aldrich) supplemented with protease and phosphatase inhibitor cocktail (Thermo Scientific). Total cellular protein concentration was determined using a BCA protein assay kit according to the manufacturer's instructions (Pierce, Thermo scientific). Total cellular proteins (20 [micro]g) were separated using 10% SDS-PAGE gel, and the separated proteins were transferred onto polyvinyl difluoride (PVDF) membrane (Bio-Rad). Nonspecific binding was blocked by incubation of the membrane in PBS with 5% nonfat dried milk and 0.1% Tween-20 for 1 h at room temperature. The membranes were probed with primary antibodies for 2 h at room temperature, [beta]-actin was used as loading control. Appropriate HRP-conjugated secondary antibodies were used to visualize the specific bands. The protein bands were visualized using ECL (Bio-Rad) according to the manufacturer's instruction. The images were taken using Chemi-Doc[TM] MP (Bio-Rad). Densitometry analyses were performed using Image Lab 5.1 (Bio-Rad).
The density of each band on the Western blots was measured using Image Lab 5.1 software (Bio-Rad). Quantitative data obtained from Western blots were subjected to statistical analysis. Significance of the differences between control and PE was calculated by Student's t-test using the Sigmaplot 12 software package (Systat Software Inc, California, USA). p<0.05 was considered as statistically significant.
In this study, we investigated the expression patterns of ADAMTSs and HAPLNs gene family in preeclamptic and control placentas. Patients were approximately matched for age, gestational age, and body mass index with control pregnant women (Table 1). The expression levels of ADAMTS-4, ADAMTS-8, ADAMTS-10, AD-AMTS-13, and ADAMTS-14 were found to be significantly lower in preeclamptic placentas than in control placentas (Figure 1). Moreover, the expression level of ADAMTS-16 was found to be higher in control placentas than in PE placentas Figure 2a, 2d). There was also a statistically significant decrease in the expression levels of ADAMTS-12 and ADAMTS-19 in preeclamptic placentas compared with those in control women placentas (Figure 2b, 2c, 2e, 2f). Although most of the ADAMTS subtypes exhibited a similar pattern with decreased expression levels in preeclamptic placentas, the expression level of ADAMTS-18 appeared to be significantly higher in preeclamptic placentas than in controls (Figure 3a, 3c). We also examined the expression levels of ADAMTS-1, ADAMTS-2, ADAMTS-7, and ADAMTS-15, but they were not expressed at detectable levels in both control and preeclamptic placentas (data not shown).
ADAMTSs show restricted susceptibility to inhibition by the four tissue inhibitors of metalloproteinases (TIMPs). TIMP-3 is the only member of the TIMP family that specifically inhibits the enzymatic activities of ADAMTS proteases. We examined the expression level of TIMP-3 to understand the reason behind reduced expression of the ADAMTS proteases. The result showed that while there was no detectable expression of TIMP-3 in control placentas, the expression level of TIMP-3 dramatically increased in preeclamptic placentas (Figure 3b).
Then, we investigated whether the expression of HAPLNs (HAP-LN-1, -2, and -4), which are the molecular partners of ADAMTSs involved in the remodeling of ECM, was altered in preeclamptic placentas. The result revealed that preeclamptic placentas exhibited high levels of HAPLN-1 and HAPLN-2; however, a very low basal expression of HAPLN-1 and HAPLN-2 was detected in control placentas (Figure 4). In addition, while high expression of HAPLN-4 was found in preeclamptic placenta, there was no observable expression of HAPLN-4 in control placenta (Figure 4).
In the present study, we reported here for the first time the expression patterns of all ADAMTS subtypes and their molecular partners, TIMP-3 and HAPLNs, in preeclamptic placentas. We showed that the expression levels of HAPLNs (-1, -2, and -4), AD-AMTS-18, and TIMP-3 were significantly higher, whereas the expression levels of ADAMTS-4, -8, -10, -12, -13, -14, -16, and -19 were significantly lower in preeclamptic placentas than in controls.
Placentation requires release of special MMPs, trophoblast invasion, and spiral arteries remodeling, as well as the eventual embodiment of ECM structure (3). Two interrelated but discrete factors, poor trophoblast invasion and inadequate spiral artery remodeling, are typical characteristics of PE (21, 22). ADAMTSs are involved in the degradation and reassembly of the ECM process (14), which is required for trophoblast invasion and spiral arteries remodeling in normal placental development. The expression of ADAMTS-1, -2, -4, -5, -6, -7, -9, -10, and -12 subtypes has been observed in the human placenta (15, 16, 23-26). Owing to their expression in the placenta and their functional significance during ECM remodeling, ADAMTSs and their molecular partners are likely to be implicated in the pathogenesis of PE.
A study reported that ADAMTS-12 is abundantly expressed in invasive human trophoblastic cells, and the decreased or abolished expression of ADAMTS-12 leads to a decrease in the invasive behavior of the trophoblastic cells, indicating that ADAMTS-12 is critical in the regulation of trophoblast invasion (10). They also showed that ADAMTS-12 promotes trophoblast invasion independently from its enzymatic activity as the catalytically dead ADAMTS-12 expression is shown to elevate the invasive capacity of the trophoblast cells (10). A further study reported that the levels of ADAMTS-12 in the serum of patients with PE are considerably reduced (27). Consistent with earlier results about ADAMTS-12, our results revealed that not only ADAMTS-12 but also ADAMTS-4, -8, -10, -13, -14, -16, and -19 protein levels were reduced in preeclamptic placentas. To the best of our knowledge, this is the first comprehensive study that evaluated ADAMTS subtype protein levels in preeclamptic placental tissues.
A study reported that ADAMTS-13 has the capacity to facilitate angiogenesis when it is in its full-length form and promotes tube formation, proliferation, and migration of human umbilical vein endothelial cells (28). In the present study, we have identified that ADAMTS-13 was highly expressed in control placenta, whereas preeclamptic placentas showed a drastically reduced expression level of ADAMTS-13. Failure of placental angiogenesis and vasculogenesis leads to abnormal placental development associated with the pathogenesis of PE. This result suggests that reduced AD-AMTS-13 expression level plays a role in impaired angiogenesis in preeclamptic placentas.
In reference to genome-wide association studies, ADAMTS-16 has been perceived as a candidate locus linked with hypertension (29). Targeted disruption of ADAMTS-16 gene in a rat model shows a significant function of ADAMTS-16 in the regulation of blood pressure (30). In our study, we found that the expression of AD-AMTS-16 was downregulated in preeclamptic placenta. Further investigation is required to clarify the link between ADAMTS-16 and hypertension in patients with preeclampsia.
Both malignant tumors and trophoblast implantation employ identical biochemical mediators in overseeing invasion (11). Dysregulation of the finely controlled process of trophoblast invasion can lead to a wide spectrum of pregnancy abnormalities including PE (11). Mutations in ADAMTS-18 gene, and methylation of promoter region of ADAMTS-18 gene are highly linked to several tumors, indicating that ADAMTS-18 acts as a tumor suppressor gene (31-33). In our study, ADAMTS-18 was the only ADAMTS subtype with significantly elevated expression in preeclamptic placentas. Our result suggested that ADAMTS-18 have an active role in the prevention of trophoblast invasion in a way similar to the mechanism of tumor suppression. However, a study reported that the maternal serum concentrations of ADAMTS-18 do not differ between women with preeclampsia and controls (27). It is possible that the variation in ADAMTS-18 expression level resulted from different tissue samples, such as maternal blood and placenta. Thus, further investigation may be helpful to clarify the exact role of ADAMTS-18 in preeclampsia.
ADAMTS proteases show restricted susceptibility to inhibition by four TIMPs. TIMP-3 is the only family member that most efficiently inhibits the enzymatic activities of ADAMTS proteases (12). There are a number of placenta-related diseases associated with the overexpression of TIMP-3, and abnormal TIMP-3 methylation in preeclampsia is capable of revealing the engagement of TIMP-3 in trophoblast invasion (34-36). As the failure of trophoblast invasion has been associated with PE, it is likely that TIMP-3 is involved in the pathophysiology of PE, which is supported by our study which shows overexpression of TIMP-3 in preeclamptic placentas. However, in another study, the expression of TIMP-3 is shown to be lower in preeclamptic placentas than in normal placentas (37). It is possible that the variation in TIMP-3 expression could result from different gestational ages of the placentas derived from patients with preeclampsia. In addition, these different results might be attributed to the effect of patient properties and different laboratory conditions. Further investigations are needed to clarify the exact role of TIMP-3 in the pathophysiology of PE.
The expression of ADAMTS subtypes and their relation with the expression levels of HAPLNs in preeclamptic placentas were examined for the first time in the present study. Our study revealed that HAPLN-1, HAPLN-2, as well as HAPLN-4 were predominantly expressed in preeclamptic placentas in comparison with control placentas. Current evidence indicates that HAPLNs may be the key components in the hyaluronic acid (HA)-based matrix scaffold organization (38). HAPLN-1 is highly renowned in stabilizing HA-proteoglycan interactions (39), for instance, versican and aggrecan degraded by ADAMTSs (20). Nonetheless, elevated expression of HAPLNs and lecticans within the adult central nervous system spatially and temporally relates with variations in ECM solubility as well as with entrance of ECM aggregates within neuron subsets, identified as "perineuronal nets." Such deviations have been linked with limited cellular motility and minimized synaptic plasticity (40). Remarkably, both HAPLN-2 and HAPLN-4 link proteins have only been identified in neural tissue (19). Furthermore, attenuated expression of HAPLNs in malignant gliomas (38) results in similar characteristics with trophoblastic invasion, suggesting that HAPLNs are an important factor for normal placentation, which failures in PE.
It is important to note that the placental tissue was consistently obtained from the same site of the placenta in both patient and control groups. The limitation of the present study is that the tissue samples were collected from only one site of the placenta which may not be a good cross-sectional representation of the whole placenta.
Our study suggests that ADAMTSs and their molecular partners, TIMP-3 and HAPLNs, might be related to the placental dysfunction in the context of PE.
Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee of Dicle University.
Informed Consent: Written informed consent was obtained from patients and control groups who participated in this study.
Peer-review: Externally peer-reviewed.
Author Contributions: Conceived and designed the experiments: SIK. Performed the experiments: IIT, GP, MAT. Analyzed the data: SIK, IIT, KD. Wrote the paper: SIK, IIT. All authors have read and approved the final manuscript.
Acknowledgements: The authors thank Dr Muberra Namh Kalem for providing placental tissue samples.
Conflict of Interest: Authors have no conflicts of interest to declare.
Financial Disclosure: The authors declared that this study has received no financial support.
(1.) Roberts JM, August PA, Bakris G, Barton JR, Bernstein IM, Druzin M, et al. Hypertension in Pregnancy Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstetrics and Gynecology 2013; 122(5): 1122-31.
(2.) Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011; 25(4): 391-403. [CrossRef]
(3.) Hu WT, Li MQ, Liu W, Jin LP, Li DJ, Zhu XY. IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-kappaB and ERK1/2 signaling. Mol Hum Reprod 2014; 20(4): 358-72. [CrossRef]
(4.) Zhou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? J Clin Invest 1997; 99(9): 2152-64. [CrossRef]
(5.) Zhou Y, Damsky CH, Chiu K, Roberts JM, Fisher SJ. Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J Clin Invest 1993; 91(3): 950-60. [CrossRef]
(6.) Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994; 101(8): 669-74. [CrossRef]
(7.) Brosens I, Pijnenborg R, Vercruysse L, Romero R. The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol 2011; 204(3): 193-201. [CrossRef]
(8.) MacCalman CD, Getsios S, Chen GT. Type 2 cadherins in the human endometrium and placenta: their putative roles in human implantation and placentation. Am J Reprod Immunol 1998; 39(2): 96-107. [CrossRef]
(9.) Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness. Placenta 2006; 27(8): 783-93. [CrossRef]
(10.) Beristain AG, Zhu H, Leung PC. Regulated expression of AD-AMTS-12 in human trophoblastic cells: a role for ADAMTS-12 in epithelial cell invasion? PLoS One 2011; 6(4): el8473. [CrossRef]
(11.) Zhu JY, Pang ZJ, Yu YH. Regulation of trophoblast invasion: the role of matrix metalloproteinases. Rev Obstet Gynecol 2012; 5(3-4): e137-43.
(12.) Kelwick R, Desanlis I, Wheeler GN, Edwards DR. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome Biol 2015; 16: 113. [CrossRef]
(13.) Tortorella MD, Malfait F, Barve RA, Shieh HS, Malfait AM. A review of the ADAMTS family, pharmaceutical targets of the future. Curr Pharm Des 2009; 15(20): 2359-74. [CrossRef]
(14.) Demircan K, Comertoglu I, Akyol S, Yigitoglu BN, Sarikaya E. A new biological marker candidate in female reproductive system diseases: Matrix metalloproteinase with thrombospondin motifs (ADAMTS). J Turk Ger Gynecol Assoc 2014; 15(4): 250-5. [CrossRef]
(15.) Lee SY, Lee HS, Gil M, Kim CJ, Lee YH, Kim KR, et al. Differential expression patterns of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) -1, -4, -5, and -14 in human placenta and gestational trophoblastic diseases. Arch Pathol Lab Med 2014; 138(5): 643-50. [CrossRef]
(16.) Hurskainen TL, Hirohata S, Seldin MF, Apte SS. ADAM-TS5, AD-AM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family. J Biol Chem 1999; 274(36): 25555-63. [CrossRef]
(17.) Brown HM, Dunning KR, Robker RL, Boerboom D, Pritchard M, Lane M, et al. ADAMTS1 cleavage of versican mediates essential structural remodeling of the ovarian follicle and cumulus-oocyte matrix during ovulation in mice. Biol Reprod 2010; 83(4): 549-57. [CrossRef]
(18.) Romao M, Weel IC, Lifshitz SJ, Peracoli MT. Elevated hyaluronan and extracellular matrix metalloproteinase inducer levels in women with preeclampsia. Arch Gynecol Obstet 2014; 289(3): 575-9. [CrossRef]
(19.) Spicer AP, Joo A, Bowling RA, Jr. A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. J Biol Chem 2003; 278(23): 21083-91. [CrossRef]
(20.) Miwa HE, Gerken TA, Huynh TD, Flory DM, Hering TM. Mammalian expression of full-length bovine aggrecan and link protein: formation of recombinant proteoglycan aggregates and analysis of proteolytic cleavage by ADAMTS-4 and MMP-13. Biochim Biophys Acta 2006; 1760(3): 472-86. [CrossRef]
(21.) Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003; 69(1): 1-7. [CrossRef]
(22.) Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27(9-10): 939-58. [CrossRef]
(23.) Abbaszade I, Liu RQ, Yang F, Rosenfeld SA, Ross OH, Link JR, et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem 1999; 274(33): 23443-50. [CrossRef]
(24.) Llamazares M, Cal S, Quesada V, Lopez-Otin C. Identification and characterization of ADAMTS-20 defines a novel subfamily of metalloproteinases-disintegrins with multiple thrombospondin-1 repeats and a unique GON domain. J Biol Chem 2003; 278(15): 13382-9. [CrossRef]
(25.) Somerville RP, Longpre JM, Jungers KA, Engle JM, Ross M, Evanko S, et al. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J Biol Chem 2003; 278(11): 9503-13. [CrossRef]
(26.) Somerville RP, Jungers KA, Apte SS. Discovery and characterization of a novel, widely expressed metalloprotease, ADAMTS10, and its proteolytic activation. J Biol Chem 2004; 279(49): 51208-17. [CrossRef]
(27.) Irem Eda Gokdemir OO, Burak Elmas, Esma Sarikaya,, Aytekin Tokmak FHK, Sumeyye Gok, Salim Erkaya, Kadir, Demircan. Evaluation of ADAMTS12, ADAMTS16, ADAMTS18 and IL-33 serum levels in pre-eclampsia. The Journal of Maternal-Fetal & Neonatal Medicine 2016; 29: 2451-6.
(28.) Lee M, Rodansky ES, Smith JK, Rodgers GM. ADAMTS13 promotes angiogenesis and modulates VEGF-induced angiogenesis. Microvasc Res 2012; 84(2): 109-15. [CrossRef]
(29.) Joe B, Saad Y, Dhindaw S, Lee NH, Frank BC, Achinike OH, et al. Positional identification of variants of Adamts16 linked to inherited hypertension. Hum Mol Genet 2009; 18(15): 2825-38. [CrossRef]
(30.) Gopalakrishnan K, Kumarasamy S, Abdul-Majeed S, Kalinoski AL, Morgan EE, Gohara AF, et al. Targeted disruption of Adamts16 gene in a rat genetic model of hypertension. Proc Natl Acad Sci USA 2012; 109(50): 20555-9. [CrossRef]
(31.) Jin H, Wang X, Ying J, Wong AH, Li H, Lee KY, et al. Epigenetic identification of ADAMTS 18 as a novel 16q23.1 tumor suppressor frequently silenced in esophageal, nasopharyngeal and multiple other carcinomas. Oncogene 2007; 26(53): 7490-8. [CrossRef]
(32.) Li Z, Zhang W, Shao Y, Zhang C, Wu Q, Yang H, et al. High-resolution melting analysis of ADAMTS 18 methylation levels in gastric, colorectal and pancreatic cancers. Med Oncol 2010; 27(3): 998-1004. [CrossRef]
(33.) Wei X, Prickett TD, Viloria CG, Molinolo A, Lin JC, Cardenas-Navia I, et al. Mutational and functional analysis reveals ADAMTS 18 metalloproteinase as a novel driver in melanoma. Mol Cancer Res 2010; 8(11): 1513-25. [CrossRef]
(34.) Feng H, Cheung AN, Xue WC, Wang Y, Wang X, Fu S, et al. Down-regulation and promoter methylation of tissue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol 2004; 94(2): 375-82. [CrossRef]
(35.) Yuen RK, Penaherrera MS, von Dadelszen P, McFadden DE, Robinson WP. DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia. Eur J Hum Genet 2010; 18(9): 1006-12. [CrossRef]
(36.) Xiang Y, Zhang X, Li Q, Xu J, Zhou X, Wang T, et al. Promoter hypomethylation of TIMP3 is associated with pre-eclampsia in a Chinese population. Mol Hum Reprod 2013;19(3):153-9. [CrossRef]
(37.) Ma R, Gu B, Gu Y, Groome LJ, Wang Y. Down-regulation of TIMP3 leads to increase in TACE expression and TNFalpha production by placental trophoblast cells. Am J Reprod Immunol 2014; 71(5): 427-33. [CrossRef]
(38.) Sim H, Hu B, Viapiano MS. Reduced expression of the hyaluronan and proteoglycan link proteins in malignant gliomas. J Biol Chem 2009; 284(39): 26547-56. [CrossRef]
(39.) Rodriguez E, Roughley P. Link protein can retard the degradation of hyaluronan in proteoglycan aggregates. Osteoarthritis Cartilage 2006; 14(8): 823-9. [CrossRef]
(40.) Rauch U. Extracellular matrix components associated with remodeling processes in brain. Cell Mol Life Sci 2004; 61(16): 2031-45. [CrossRef]
Sevgi Irtegun Kandemir (1), Irmak Igen Taskin (2), Gulsum Pektang (1), Mehmet Ali Tekin (1), Kadir Demircan (3)
Cite this article as: irtegun Kandemir S, Icen Taskin I, Pektanc G, Tekin MA, Demircan K. Altered Expression of ADAMTSs and HAPLNs in Preeclamptic Placenta. Erciyes Med J 2018; 40(2): 87-92
(1) Department of Medical Biology, Dicle University Facu Ity of Med icine, Diyarbakir, Turkey
(2) Department of Biology, Firat University Faculty of Science, Elazig, Turkey
(3) Department of Molecular Biology and Biochemistry, Okayama University Faculty of Medicine, Okayama, Japan
Correspondence Sevgi irtegun Kandemir, Department of Med ical Biology, Dicle University Facu Ity of Med icine, Diyarbakir, Turkey Phone: 041 2 241 10 00 e-mail: firstname.lastname@example.org
Table 1. Demographic and clinical characteristics of the study groups Preeclampsia Control Characteristics (n=10) (n=10) Maternal age (years) 28.4[+ or -]5.7 29.4[+ or -]3.8 Gestational age (week) 32.6[+ or -]3.35 33.7[+ or -]4.2 Body mass index (kg/m2) 23.85[+ or -]3.63 22.7[+ or -]2.62 Systolic blood pressure (mm Hg) 161.3[+ or -]18 119.6[+ or -]6.4 Diastolic blood pressure (mm Hg) 105.5[+ or -]15 73.6[+ or -]5.9 Proteinuria (g/24 h) 0.42[+ or -]0.13 - Mode of delivery Cesarean section Cesarean section Characteristics (*) P Maternal age (years) 0.518 Gestational age (week) 0.197 Body mass index (kg/m2) 0.521 Systolic blood pressure (mm Hg) <0.001 Diastolic blood pressure (mm Hg) <0.001 Proteinuria (g/24 h) - Mode of delivery Data are shown as mean[+ or -]s.d. (*) p-Values <0.05 are represented in boldface.
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Kandemir, Sevgi Irtegun; Taskin, Irmak Igen; Pektang, Gulsum; Tekin, Mehmet Ali; Demircan, Kadir|
|Publication:||Erciyes Medical Journal|
|Date:||Jun 1, 2018|
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