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2. PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer

Author

Su, Y, Loos, M, Giese, N, Hines, OJ, Diebold, I, Görlach, A, Metzen, E, Pastorekova, S, Friess, H, and Büchler, P

Subjects
Digestive Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Animals, Annexin A5, Apoptosis, Carcinoma, Pancreatic Ductal, Caspase 3, Cell Differentiation, Cell Line, Tumor, Dioxygenases, Enzyme-Linked Immunosorbent Assay, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Neoplasm Invasiveness, Neovascularization, Pathologic, Pancreatic Neoplasms, Polymerase Chain Reaction, RNA, Messenger, RNA, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Up-Regulation, Vascular Endothelial Growth Factor A, angiogenesis, HIF-1, hypoxia, pancreatic cancer, PHD3, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

PurposeTumour hypoxia activates hypoxia-inducible factor-1 (HIF-1) and indluences angiogenesis, cell survival and invasion. Prolyl hydroxylase-3 (PHD3) regulates degradation of HIF-1α. The effects of PHD3 in tumour growth are largely unknown.Experimental designPHD3 expression was analysed in human pancreatic cancer tissues and cancer cell lines by real-time quantitative PCR and immunohistochemistry. PHD3 overexpression was established by stable transfection and downregulation by short interfering RNA technology. VEGF was quantified by enzyme-linked immunosorbent assay. Matrigel invasion assays were performed to examine tumour cell invasion. Apoptosis was measured by annexin-V staining and caspase-3 assays. The effect of PHD3 on tumour growth in vivo was evaluated in an established orthotopic murine model.ResultsPHD3 was upregulated in well-differentiated human tumours and cell lines, and regulated hypoxic VEGF secretion. PHD3 overexpression mediated tumour cell growth and invasion by induction of apoptosis in a nerve growth factor-dependent manner by the activation of caspase-3 and phosphorylation of focal adhesion kinase HIF-1 independently. In vivo, PHD3 inhibited tumour growth by abrogation of tumour angiogenesis.ConclusionOur results indicate essential functions of PHD3 in tumour growth, apoptosis and angiogenesis and through HIF-1-dependent and HIF-1-independent pathways.

Published
2010

13. Characterization of carbonic anhydrase in interactome reveals proteins assisting its nuclear localization in hypoxic cells

Author

Buanne P, Renzone G, Monteleone F, Vitale M, Monti SM, Sandomenico A, Garbi C, Montanaro D, Troncone G, Zaticova M, Csaderova L, Supuran CT, Pastorekova S, Scaloni A, De Simone G, zambrano N., ACCARDO, Marina, Buanne, P, Renzone, G, Monteleone, F, Vitale, M, Monti, Sm, Sandomenico, A, Garbi, C, Montanaro, D, Accardo, Marina, Troncone, G, Zaticova, M, Csaderova, L, Supuran, Ct, Pastorekova, S, Scaloni, A, De Simone, G, and Zambrano, N.

Published
2013

14. Absence of keratin 1 restricts the course of infection with lymphocytic choriomeningitis virus strain MX.

Author

LABUDOVA, M., ZDURIENCIKOVA, M., FABIANOVA, A., BARATOVA, M., DITTE, P., RADVAK, P., NEMCOVICOVA, I., PASTOREKOVA, S., and PASTOREK, J.

Subjects
LYMPHOCYTIC choriomeningitis, KERATIN, RNA viruses, IMMUNOFLUORESCENCE, SMALL interfering RNA
Abstract

A rodent-transmitted enveloped lymphocytic choriomeningitis virus (LCMV) is an RNA virus causing persistent infection. During persistent infection, a unique strain MX of LCMV does not yield infectious virions, therefore it is not able to use a receptor for its dissemination, and spreads by cell-to-cell contacts. Virus can be transported to the neighboring cell by different cellular structures such as tunneling nanotubes or cytonemes. Using q-PCR, immunofluorescence, siRNA and western blot, we show that keratin 1 (K1) is essential for the persistent infection caused by LCMV strain MX, and its absence very effectively slows down the course of infection. In contrast, other LCMV strains, namely Clone 13 and Armstrong, which produce expression of K1, desmosomes in cells expressing K1 (42-MG-BA) but not in cells without K1 expression (NIH/3T3). We conclude that the presence of the virus enhances the K1 expression, while the presence of K1 protein potentiates the viral spread in persistently infected cells. [ABSTRACT FROM AUTHOR]

Published
2019
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15. Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX

Author

Alterio V, Hilvo M, Di Fiore A, Supuran C.T., Pan P, Parkkil S, Scaloni A, Pastorek J, Pastorekova S, Scozzafava A, Monti SM, De Simone G., PEDONE, CARLO, Alterio, V, Hilvo, M, Di Fiore, A, Supuran, C. T., Pan, P, Parkkil, S, Scaloni, A, Pastorek, J, Pastorekova, S, Pedone, Carlo, Scozzafava, A, Monti, Sm, and De Simone, G.

Abstract

Carbonic anhydrase (CA) IX is a plasma membrane-assocd. member of the .alpha.-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here, we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clin. used sulfonamide inhibitor, acetazolamide. The structure reveals a typical .alpha.-CA fold, which significantly differs from the other CA isoenzymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX assoc. to form a dimer, which is stabilized by the formation of an intermol. disulfide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the three-dimensional structure and the physiol. role of the enzyme is suggested, based on the measurement of the pH profile of the catalytic activity for the physiol. reaction, CO2 hydration to bicarbonate and protons. On the basis of the structural differences obsd. between CA IX and the other membrane-assocd. .alpha.-CAs, further prospects for the rational drug design of isoenzyme- specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.

Published
2009

23. Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

Author

Ebbesen, P, Pettersen, E O, Gorr, T A, Jobst, G, Williams, K, Kieninger, J, Wenger, R H, Pastorekova, S, Dubois, L, Lambin, P, Wouters, B G, Van den Beucken, T, Beucken, D, Supuran, C T, Poellinger, L, Ratcliffe, P, Kanopka, A, Görlach, A, Gassmann, M, Harris, A L, Maxwell, P, Scozzafava, A, University of Zurich, and Ebbesen, P

Subjects
3004 Pharmacology, 10076 Center for Integrative Human Physiology, 3002 Drug Discovery, 570 Life sciences, biology, 610 Medicine & health, 10081 Institute of Veterinary Physiology, 10052 Institute of Physiology
Published
2009
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26. Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas

Author

Shankavaram, U., Fliedner, S.M., Elkahloun, A.G., Barb, J.J., Munson, P.J., Huynh, T.T., Matro, J.C., Turkova, H., Linehan, W.M., Timmers, H.J.L.M., Tischler, A.S., Powers, J.F., Krijger, R. de, Baysal, B.E., Takacova, M., Pastorekova, S., Gius, D., Lehnert, H., Camphausen, K., Pacak, K., Shankavaram, U., Fliedner, S.M., Elkahloun, A.G., Barb, J.J., Munson, P.J., Huynh, T.T., Matro, J.C., Turkova, H., Linehan, W.M., Timmers, H.J.L.M., Tischler, A.S., Powers, J.F., Krijger, R. de, Baysal, B.E., Takacova, M., Pastorekova, S., Gius, D., Lehnert, H., Camphausen, K., and Pacak, K.

Abstract

Contains fulltext : 118484.pdf (publisher's version ) (Open Access), Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e.g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r = 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies.

Published
2013

27. Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas

Author

Shankavaram, U. (Uma), Fliedner, S.M.J. (Stephanie), Elkahloun, A.G. (Abdel), Barb, J.J. (Jenifer), Munson, P.J. (Peter), Huynh, T.T. (Thanh), Matro, J.C. (Joey), Turkova, H. (Hana), Marston Linehan, W., Timmers, H.J.L.M. (Henri), Tischler, A.S. (Arthur), Powers, J.F. (James), Krijger, R.R. (Ronald) de, Baysal, B.E. (Bora), Takacova, M. (Martina), Pastorekova, S. (Silvia), Gius, D. (David), Lehnert, H. (Hendrik), Camphausen, K. (Kevin), Pacak, K. (Karel), Shankavaram, U. (Uma), Fliedner, S.M.J. (Stephanie), Elkahloun, A.G. (Abdel), Barb, J.J. (Jenifer), Munson, P.J. (Peter), Huynh, T.T. (Thanh), Matro, J.C. (Joey), Turkova, H. (Hana), Marston Linehan, W., Timmers, H.J.L.M. (Henri), Tischler, A.S. (Arthur), Powers, J.F. (James), Krijger, R.R. (Ronald) de, Baysal, B.E. (Bora), Takacova, M. (Martina), Pastorekova, S. (Silvia), Gius, D. (David), Lehnert, H. (Hendrik), Camphausen, K. (Kevin), and Pacak, K. (Karel)

Abstract

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e.g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r= 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies.

Published
2013
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28. Genotype and Tumor Locus Determine Expression Profile of Pseudohypoxic Pheochromocytomas and Paragangliomas

Author

Shankavaram, U, Fliedner, SMJ, Elkahloun, AG, Barb, JJ, Munson, PJ, Huynh, TT, Matro, JC, Turkova, H, Linehan, WM, Timmers, HJ, Tischler, AS, Powers, JF, de Krijger, Ronald, Baysal, BE, Takacova, M, Pastorekova, S, Gius, D, Lehnert, H, Camphausen, K, Pacak, K, Shankavaram, U, Fliedner, SMJ, Elkahloun, AG, Barb, JJ, Munson, PJ, Huynh, TT, Matro, JC, Turkova, H, Linehan, WM, Timmers, HJ, Tischler, AS, Powers, JF, de Krijger, Ronald, Baysal, BE, Takacova, M, Pastorekova, S, Gius, D, Lehnert, H, Camphausen, K, and Pacak, K

Abstract

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e. g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r = 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies.

Published
2013

29. PHD oxygen sensor function and antioxidants

Author

Pastorekova, Silvia, Kopacek, Juraj, Pastorekova, S ( Silvia ), Kopacek, J ( Juraj ), Nytko, K J, Stiehl, D P, Wenger, R H, Pastorekova, Silvia, Kopacek, Juraj, Pastorekova, S ( Silvia ), Kopacek, J ( Juraj ), Nytko, K J, Stiehl, D P, and Wenger, R H

Published
2012

30. Hypoxia-induced expression of carbonic anhydrase 9 is dependent on the unfolded protein response.

Author

Beucken, T. van den, Koritzinsky, M., Niessen, H., Dubois, L., Savelkouls, K., Mujcic, H., Jutten, B., Kopacek, J., Pastorekova, S., Kogel, A.J. van der, Lambin, P., Voncken, W., Rouschop, K.M., Wouters, B.G., Beucken, T. van den, Koritzinsky, M., Niessen, H., Dubois, L., Savelkouls, K., Mujcic, H., Jutten, B., Kopacek, J., Pastorekova, S., Kogel, A.J. van der, Lambin, P., Voncken, W., Rouschop, K.M., and Wouters, B.G.

Abstract

Contains fulltext : 80413.pdf (Publisher’s version ) (Open Access), Adaptation to tumor hypoxia is mediated in large part by changes in protein expression. These are driven by multiple pathways, including activation of the hypoxia inducible factor-1 (HIF-1) transcription factor and the PKR-like endoplasmic reticulum kinase PERK, a component of the unfolded protein response. Through gene expression profiling we discovered that induction of the HIF-1 target gene CA9 was defective in mouse embryo fibroblasts derived from mice harboring an eIF2alpha S51A knock-in mutation. This finding was confirmed in two isogenic human cell lines with an engineered defect in eIF2alpha phosphorylation. We show that impaired CA9 expression was not due to changes in HIF activity or CA9 mRNA stability. Using chromatin immunoprecipitation we show that the eIF2alpha-dependent translationally regulated gene ATF4 binds directly to the CA9 promoter and is associated with loss of the transcriptional repressive histone 3 lysine 27 tri-methylation mark. Loss or overexpression of ATF4 confirmed its role in CA9 induction during hypoxia. Our data indicate that expression of CA9 is regulated through both the HIF-1 and unfolded protein response hypoxia response pathways in vitro and in vivo.

Published
2009

31. Identifikation von prädiktiven Biomarkern für Hyperthermie und Re-Bestrahlung beim loko-regionären Rezidiv des Mammakarzinoms

Author

Farr, A, primary, Wuerstlein, R, additional, Neff, J, additional, Issels, R, additional, Lindner, L, additional, Belka, C, additional, Lauber, K, additional, Rauch, J, additional, Scheithauer, H, additional, Salat, C, additional, Pastorekova, S, additional, Takacova, M, additional, Friese, K, additional, and Harbeck, N, additional

Published
2013
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40. Carbonic anhydrase IX antigen differentiates between preneoplastic malignant lesions in non-small cell lung carcinoma.

Author

Vermylen, P, Roufosse, Caroline, Burny, Arsène, Verhest, Alain, Bosschaerts, Tom, Pastorekova, S, Ninane, V, Sculier, Jean-Paul, Vermylen, P, Roufosse, Caroline, Burny, Arsène, Verhest, Alain, Bosschaerts, Tom, Pastorekova, S, Ninane, V, and Sculier, Jean-Paul

Abstract

The MaTu interval (MN)/carbonic anhydrase (CA) IX tumour-associated antigen is a protein that is normally expressed in the gut and belongs to the carbonic anhydrase enzyme family (CA IX). It has been detected in tumour cell lines and in some solid tumours including cervical, oesophageal and clear cell renal carcinoma. This study determined MN/CA IX expression in 65 primary non-small cell lung cancer resected with curative intent and in 38 bronchial preneoplastic lesions, carcinoma in situ or microinvasive carcinoma as well as in normal bronchial tissue. The presence of MN/CA IX was detected using immunohistochemistry and Western blot analysis, whenever frozen material was available. Immunostaining was positive in 52/65 (80%) of the tumour samples. The staining was more often focal than diffuse. The percentage of stained cells in positive tumours was highly variable, ranging 1-85%. The pattern of immunostaining was predominantly cytoplasmic with a membranous reinforcement (87%). The intensity was mainly strong (69%). The presence of the protein in the tumour was confirmed by Western blot analysis in the eight samples tested. All the morphologically normal epithelia, except in close vicinity of tumours in some cases, as well as the preneoplastic bronchial lesions (basal cell hyperplasia, metaplasia and dysplasia) were immunonegative for MN/CA IX expression. In contrast, carcinoma in situ and microinvasive epithelioma showed the presence of MN-immunopositive tumoural cells in 5/7 and 4/5 of the samples, respectively. These data suggest that MN/CA IX is a useful marker for the differentiation between preneoplastic lesions and bronchial non-small cell lung cancer in the lung., Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
1999

48. Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype.

Author

Barathova, M., Takacova, M., Holotnakova, T., Gibadulinova, A., Ohradanova, A., Zatovicova, M., Hulikova, A., Kopacek, J., Parkkila, S., Supuran, C. T., Pastorekova, S., and Pastorek, J.

Subjects
HYPOXEMIA, CARBONIC anhydrase, CANCER, TUMORS, PHENOTYPES, ACIDOSIS, CELLS
Abstract

CA IX is a hypoxia-induced, cancer-associated carbonic anhydrase isoform with functional involvement in pH control and cell adhesion. Here we describe an alternative splicing variant of the CA9 mRNA, which does not contain exons 8–9 and is expressed in tumour cells independently of hypoxia. It is also detectable in normal tissues in the absence of the full-length transcript and can therefore produce false-positive data in prognostic studies based on the detection of the hypoxia- and cancer-related CA9 expression. The splicing variant encodes a truncated CA IX protein lacking the C-terminal part of the catalytic domain. It shows diminished catalytic activity and is intracellular or secreted. When overexpressed, it reduces the capacity of the full-length CA IX protein to acidify extracellular pH of hypoxic cells and to bind carbonic anhydrase inhibitor. HeLa cells transfected with the splicing variant cDNA generate spheroids that do not form compact cores, suggesting that they fail to adapt to hypoxic stress. Our data indicate that the splicing variant can functionally interfere with the full-length CA IX. This might be relevant particularly under conditions of mild hypoxia, when the cells do not suffer from severe acidosis and do not need excessive pH control.British Journal of Cancer (2008) 98, 129–136. doi:10.1038/sj.bjc.6604111 www.bjcancer.com Published online 20 November 2007 [ABSTRACT FROM AUTHOR]

Published
2008
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49. Hypoxia modulates gene expression of IP3 receptors in rodent cerebellum.

Author

Jurkovicova, D., Kopacek, J., Stefanik, P., Kubovcakova, L., Zahradnikova Jr, A., Pastorekova, S., and Krizanova, O

Subjects
CEREBRAL anoxia, GENE expression, CALCIUM channels, BRAIN diseases, CEREBROVASCULAR disease
Abstract

Hypoxic brain cell injury is a complex process that results from a series of intracellular events. In this work, we tested whether severe hypoxia for 6 h can affect gene expression and protein levels of intracellular calcium channels, ryanodine receptors, and inositol 1,4,5-trisphosphate receptors in mouse cerebellum. In addition, we tested the effect of hypoxia on cerebellar granular cells of rats. We have found that gene expression of types 1 and 2 IP3 receptors is significantly increased after the exposure of mice to hypoxic stimulus for 6 h and also in rat cerebellar granular cells. Increased gene expression of IP3 receptors was reflected in increased protein levels of these channels as well. In this process, reactive oxygen species are most probably involved, as antioxidant quercetin abolished hypoxia-induced increase in both types 1 and 2 IP3 receptor. Ryanodine receptors of types 1 and 2 and sarco(endo)plasmic reticulum Ca2+-ATPase were not affected by hypoxia on the level of messenger RNA. To test physiological consequences, we measured levels of intracellular calcium. We observed significantly elevated calcium level in hypoxic compared to normoxic cells. Deeper understanding of mechanisms, through which hypoxia regulates intracellular calcium, could point towards the development of new therapeutic approaches to reduce or suppress the pathological effects of cellular hypoxia, such as those seen in stroke or ischemia. [ABSTRACT FROM AUTHOR]

Published
2007
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50. Modulation of expression of Na+/Ca2+ exchanger in heart of rat and mouse under stress.

Author

Hudecova, S., Kubovcakova, L., Kvetnansky, R., Kopacek, J., Pastorekova, S., Novakova, M., Knezl, V., Tarabova, B., Lacinova, L., Sulova, Z., Breier, A., Jurkovicova, D., and Krizanova, O.

Subjects
MYOCARDIAL infarction, CORONARY disease, CARDIOGENIC shock, PHYSIOLOGICAL stress, CELL membranes, BIOLOGICAL membranes, RATS
Abstract

Aim: The Na+/Ca2+ exchanger (NCX) is a major Ca2+ extrusion system in the plasma membrane of cardiomyocytes and an important component participating on the excitation–contraction coupling process in muscle cells. NCX1 isoform is the most abundant in the heart and is known to be changed after development of ischaemia or myocardial infarction. Objective of this study was to investigate the effect of stress factors (immobilization, cold and short-term hypoxia) on the expression of NCX1, in vivo, in the heart of rat and mouse. Methods: We compared gene expression and protein levels of control and stressed animals. The activity of NCX was measured by the whole cell configuration using the patch clamp. We also measured physiological parameters of the heart in physiological conditions and under ischaemia-reperfusion to compare response of control and stressed hearts. Results: We have found that only strong stress stimulus (hypoxia, immobilization) applied repeatedly for several days elevated the NCX1 mRNA level. Cold, which is a weaker stressor that activates mainly sympathoneural, and only marginally adrenomedullary system did not affect the gene expression of NCX1. Thus, from these results it appears that hormones produced by the adrenal medulla (mainly adrenaline) might be involved in this process. To study possible mechanism of the NCX1 regulation by stress, we focused on the possible role of the hypothalamo–pituitary–adrenocortical pathway in the activation of catecholamine synthesis in the adrenal medulla. We have already published that cortisol affects activity, but not the gene expression of NCX1. In this work, we used corticotropin-releasing hormone (CRH) knockout mice, where secretion of corticosterone and subsequently adrenaline is significantly suppressed. As no increase in NCX1 mRNA was observed in CRH knockout mice due to immobilization stress, we proposed that adrenaline (probably regulated via corticosterone) is involved in the regulation of NCX1 gene expression during stress. Conclusions: The gene expression and protein levels of the NCX1 are increased by the strong stress stimuli, e.g. hypoxia, or immobilization stress. The activity of NCX1 is decreased. Based on these results, we assume that the gene expression of NCX is increased as a consequence of suppressed activity of this transport system. [ABSTRACT FROM AUTHOR]

Published
2007
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