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  • JNK-IN-7 australia Epitope analyses of AT AA and ET AA


    Epitope analyses of AT1-AA and ET-AA indicate that the JNK-IN-7 australia of both autoantibodies are located at the second extracelluar loop of both receptors. The specific epitopes for both autoantibodies are similar to what was reported previously in a cohort of patients from Brazil [6] and for AT1-AA also from North America [20], and European patients [5]. In the bioassay the endothelin receptor autoantibodies induce a negative chronotropic effect on cardiomyocytes which is different from the effect of the Angiotensin II receptor I autoantibodies. However, the effect on the in-vitro cultures of cardiomyocytes from newborn rats may differ f\'rom the physiological effect of stimulation of the endothelin receptor on vascular smooth muscle cells. Therefore the pathophysiological effects of ETA-AA in preeclampsia are awaiting further studies. Plasma IL-17A [21], [22], [23] and Il-17 producing CD3 + CD4 + T lymphocytes [24] are reported to be increased in patients with preeclampsia. Plasma IL-17 is also increased in RUPP rats and in normal pregnant rats supplemented with CD + T cells from RUPP rats [25]. Our results show that a subgroup of patients with severe preeclampsia or HELLP syndrome express high concentrations of IL-17A, and that the same patients express high levels in blood samples from the first trimester (gestational week 8–10). Although a high concentration of IL17 was almost exclusively seen in the group of patients which developed severe preeclampsia or HELLP syndrome, a large group of patients with severe PE/HELLP expressed IL-17A below the detection limit of the assay. We did not find any significant difference in clinical or biochemical biomarkers between the two groups. Detection of IL-17A early in blood samples from gestational week 5–16 was also investigated by Salazar et al. [25], who reported that patients who later developed preeclampsia had a significantly higher percentage of CD4 + IL-17 + out of total CD4 + T cells, as compared to patients who did not develop preeclampsia. Together these results suggest that a subgroup of pregnant women displayed a proinflammatory state with an increased concentration of Th17 cells and increased Plasma IL-17A already in the first trimester, and that this is associated with the risk of developing pregnancy-induced hypertensive disorders.
    Competing interests
    Funding The study was supported by a grant from the Independent Research Fund Denmark, and Bagermester August Jensen og Hustrus legat.
    Introduction Endothelin receptor type A (EDNRA) belongs to a G protein-coupled receptor family and is a receptor for the Endothelin-1 (ET-1) protein [1]. ET-1 is expressed in a variety of cells, including vascular smooth muscle cells, cardiomyocytes, macrophages, leukocytes, and fibroblasts, but the main site of ET-1 production is endothelial cells [2]. The ET-1/EDNRA axis, known as endothelin axis is involved in a diverse range of physiological and pathophysiological processes such as vasoconstriction, and cell proliferation [3]. Aberrant expression of the ET-1/EDNRA axis in cancer cells stimulates cell proliferation, survival, angiogenesis and invasion [4]. Considering the fact that the tumor microenvironment often consists of cells which are the main sources of ET-1, the contribution of endothelin axis in tumor growth and metastasis have brought a lot of interest in investigating the function and underlying mechanisms of its tumorigenicity [5,6]. A range of specific EDNRA antagonists has recently shown promising results in some cancers [7]. So far, the majority of investigations represent a role for EDNRA in progression of solid tumors but the contribution of Ednra in hematopoietic malignancies has not been investigated. Homeodomain proteins such as HOXA9 and MEIS1 are highly expressed in hematopoietic stem and progenitor cells and their expression decreases during differentiation [8,9]. Deregulation of HOXA9/MEIS1 axis is frequent in acute leukemia and a variety of genetic alterations have been shown to sustain high expression of HOXA9 and MEIS1 and their downstream targets [10,11]. Co-expression of Hoxa9 and Meis1 results in increased transformation efficacy of hematopoietic progenitors and induction of rapidly progressing acute myeloid leukemia (AML) in mice [12,13]. Several downstream target genes of Hoxa9 and Meis1 have also been identified and investigated for their relative contribution to leukemia development (i.e. Flt3, miR155, Syk, etc.), although none have been shown as the key mediator of Hoxa9+Meis1-leukemogenesis [[14], [15], [16]]. Thus, the understanding behind the HOXA9/MEIS1-induced leukemogenesis is still incomplete.