Metabolic syndrome is a cluster of several risk factors for type 2 diabetes and cardiovascular disease, including obesity, hypertension, insulin resistance, and dyslipidemia. These pathological conditions are determined multifactorially by many genes and their interactions with environmental effects. Genome wide association studies (GWAS) in humans which are based on the “common variants – common diseases“ hypothesis identified only a minor proportion of the total heritability of complex traits so far.
Statistically significant variants (SNPs – single nucleotide polymorphisms) are typically associated with a miniscule phenotypic variability without meaningful clinical effects. Studies in animal models of human complex diseases can provide a useful alternative. Experiments with rat models can control for both genetic background and environmental effects as well as enable genetic manipulation of experimental animals. The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and associated metabolic disturbances typical for metabolic syndrome. Although it cannot be expected that the individual predisposing genes themselves might be conserved between rats and humans, it is likely that the networks and pathways of genes leading to disease susceptibility will be conserved across species. Therefore, identification of the networks and pathways of genes underlying the cellular pathology of disease phenotypes in the rat could provide insight into the pathogenesis and treatment of the corresponding human diseases.
Our research is focused on these projects:
- Identification of genes that regulate hemodynamic and metabolic traits in the SHR.
- Identification of new genes coding for mitochondrial proteins and their role in the pathogenesis of metabolic syndrome.
- Derivation of new animal models using highly effective methods for transgenesis and gene targeting.
- Study of the role of inflammatory processes and oxidative stress in the pathogenesis of metabolic syndrome and possibility of pharmacologic interventions.
Current grant support.
Projects
Recently, new highly efficient techniques become available for derivation of transgenic or knockout rats for in vivo functional studies of candidate genes for QTL, for analyses of genes with unknown function or for derivation of new rat models of human diseases.
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For genetic dissection of complex pathophysiological traits in recombinant inbred (RI) strains, it is possible to take the advantage of accumulated genotypes and intermediary phenotypes. Intermediate phenotypes have simpler genetic architectures and can be used for connecting variabilty at the DNA level with complex pathophysiological traits. Abundance of mRNA (transcriptome), proteins (proteome), metabolites (metabolome), etc. are the most widely used intermediary phenotypes.
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Candidate genes for pathophysiological traits, identified by linkage and correlation analyses with intermediary phenotypes and by their sequencing, are tested by in vivo functional analysis in transgenic rescue or knockout experiments with the aim to identify quantitative trait loci at the molecular level and analyze responsible pathophysiological mechanisms.
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We plan to identify genetic determinants of the mitochondrial proteome in relation to important complex disease traits in the rat and thereby improve understanding of the pathogenetic role of mitochondria in common clinical disorders.
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Publications
Trnovská, J. - Šilhavý, Jan - Kuda, Ondřej - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šimáková, Miroslava - Strnad, Hynek - Škop, V. - Oliyarnyk, O. - Kazdová, L. - Haluzík, M. - Pravenec, Michal
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Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls
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PLoS ONE. 2017, roč. 12, 6, článku e0179063
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IF = 2.806
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Šeda, Ondřej - Liška, F. - Pravenec, Michal - Vernerová, Z. - Kazdová, L. - Křenová, D. - Zídek, Václav - Šedová, Lucie - Krupková, M. - Křen, V.
Connexin 50 Mutation Lowers Blood Pressure in Spontaneously Hypertensive Rat
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Physiological Research. 2017, roč. 66, 1, p. 15-28
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IF = 1.461
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Svoboda, Petr - Křížová, E. - Čeňková, K. - Vápenková, K. - Zídková, J. - Zídek, Václav - Škop, V.
Visfatin Is Actively Secreted In Vitro From U-937 Macrophages, but Only Passively Released From 3T3-L1 Adipocytes and HepG2 Hepatocytes
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Physiological Research. 2017, roč. 66, 4, p. 709-714
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IF = 1.461
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Rýdlová, M. - Růnová, K. - Száková, J. - Fučíková, A. - Hakenová, A. - Mlejnek, Petr - Zídek, Václav - Tremlová, J. - Mestek, O. - Kaňa, A. - Zídková, J. - Melčová, M. - Truhlářová, K. - Tlustoš, P.
The Response of Macro- and Micronutrient Nutrient Status and Biochemical Processes in Rats Fed on a Diet with Selenium-Enriched Defatted Rapeseed and/or Vitamin E Supplementation
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BioMed Research International. 2017, roč. 2017, 2017, článku 6759810
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IF = 2.476
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Neckář, Jan - Svatoňová, Anna - Weissová, Romana - Drahota, Zdeněk - Zajíčková, Pavlína - Brabcová, I. - Kolář, D. - Alánová, Petra - Vašinová, Jana - Šilhavý, Jan - Hlaváčková, Markéta - Tauchmannová, Kateřina - Milerová, Marie - Ošťádal, Bohuslav - Červenka, L. - Žurmanová, J. - Kalous, M. - Nováková, Olga - Novotný, J. - Pravenec, Michal - Kolář, František
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Selective replacement of mitochondrial DNA increases the cardioprotective effect of chronic continuous hypoxia in spontaneously hypertensive rats
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Clinical science. 2017, roč. 131, 9, p. 865-881
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IF = 4.936
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Liška, F. - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šilhavý, Jan - Šimáková, Miroslava - Strnad, Hynek - Trnovská, J. - Škop, V. - Kazdová, L. - Starker, C.G. - Voytas, D.F. - Izsvák, Z. - Mancini, M. - Šeda, O. - Křen, V. - Pravenec, Michal
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Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat
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Hypertension. 2017, roč. 69, 6, p. 1084-1091
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IF = 6.857
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doi
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Kurtz, T. W. - DiCarlo, S. E. - Pravenec, Michal - Morris Jr., R. C.
The American Heart Association Scientific Statement on salt sensitivity of blood pressure: Prompting consideration of alternative conceptual frameworks for the pathogenesis of salt sensitivity?
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Journal of Hypertension. 2017, roč. 35, 11, p. 2214-2225
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IF = 4.085
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doi
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Kurtz, T. W. - DiCarlo, S. E. - Pravenec, Michal - Morris Jr., R. C.
An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure
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Journal of the American Heart Association. 2017, roč. 6, 4, článku e005653
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IF = 4.863
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doi
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Coan, P. M. - Hummel, O. - Diaz, A. G. - Barrier, M. - Alfazema, N. - Norsworthy, P. J. - Pravenec, Michal - Petretto, E. - Hübner, N. - Aitman, T. J.
Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat
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Disease Models & Mechanisms. 2017, roč. 10, 3, p. 297-306
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IF = 4.691
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doi
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Liška, F. - Chylíková, B. - Janků, M. - Šeda, Ondřej - Vernerová, Z. - Pravenec, Michal - Křen, Vladimír
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Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat
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Reproduction. 2016, roč. 152, 3, p. 215-223
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IF = 3.100
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doi
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Abdelmagid, N. - Bereczky-Veress, B. - Atanur, S. - Musilová, Alena - Zídek, Václav - Saba, L. - Warnecke, A. - Khademi, M. - Studahl, M. - Aurelius, E. - Hjalmarsson, A. - Garcia-Dias, A. - Denis, C. V. - Bergström, N. - Sköldenberg, B. - Kockum, I. - Aitman, T. - Hübner, N. - Olsson, T. - Pravenec, Michal - Diez, M.
Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis
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PLoS ONE. 2016, roč. 11, 5, e0155832
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IF = 2.806
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doi
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Malínská, H. - Oliyarnyk, O. - Škop, V. - Šilhavý, Jan - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šimáková, Miroslava - Strnad, Hynek - Kazdová, L. - Pravenec, Michal
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Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein
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PLoS ONE. 2016, roč. 11, 3, e0150924
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IF = 2.806
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doi
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Šedová, Lucie - Pravenec, Michal - Křenová, D. - Kazdová, L. - Zídek, Václav - Krupková, M. - Liška, F. - Křen, Vladimír - Šeda, Ondřej
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Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model
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PLoS ONE. 2016, roč. 11, 3, článku e0152708
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IF = 2.806
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doi
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Liška, F. - Peterková, Renata - Peterka, Miroslav - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šilhavý, Jan - Šimáková, Miroslava - Křen, Vladimír - Starker, C.G. - Voytas, D.F. - Izsvák, Z. - Pravenec, Michal
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Targeting of the Plzf Gene in the Rat by Transcription Activator-Like Effector Nuclease Results in Caudal Regression Syndrome in Spontaneously Hypertensive Rats
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PLoS ONE. 2016, roč. 11, 10, e0164206
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IF = 2.806
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[
doi
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Škop, V. - Trnovská, J. - Oliyarnyk, O. - Marková, I. - Malínská, H. - Kazdová, L. - Zídek, Václav - Landa, Vladimír - Mlejnek, Petr - Šimáková, Miroslava - Kůdela, M. - Pravenec, Michal - Šilhavý, Jan
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Hepatotoxic effects of fenofibrate in spontaneously hypertensive rats expressing human C-reactive protein
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Physiological Research. 2016, roč. 65, 6, p. 891-899
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IF = 1.461
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Pravenec, Michal - Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šilhavý, Jan - Mir, S.A. - Vaingankar, S. M. - Wang, J. - Kurtz, T. W.
Effects of transgenic expression of dopamine beta hydroxylase (Dbh) gene on blood pressure in spontaneously hypertensive rats
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Physiological Research. 2016, roč. 65, 6, p. 1039-1044
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IF = 1.461
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Pravenec, Michal - Mlejnek, Petr - Zídek, Václav - Landa, Vladimír - Šimáková, Miroslava - Šilhavý, Jan - Strnad, Hynek - Eigner, Sebastian - Eigner-Henke, Kateřina - Škop, V. - Malínská, H. - Trnovská, J. - Kazdová, L. - Drahota, Zdeněk - Mráček, Tomáš - Houštěk, Josef
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Autocrine effects of transgenic resistin reduce palmitate and glucose oxidation in brown adipose tissue
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Physiological Genomics. 2016, roč. 48, 6, p. 420-427
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IF = 3.044
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doi
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Wang, M. - Sips, P. - Khin, E. - Rotival, M. - Sun, X. - Ahmed, R. - Widjaja, A. A. - Schafer, S. - Yusoff, P. - Choksi, P. K. - Ko, N. S. J. - Singh, M. K. - Epstein, D. - Guan, Y. - Houštěk, Josef - Mráček, Tomáš - Nůsková, Hana - Mikell, B. - Tan, J. - Pesce, F. - Kolář, František - Bottolo, L. - Mancini, M. - Hubner, N. - Pravenec, Michal - Petretto, E. - MacRae, C. - Cook, S. A.
Wars2 is a determinant of angiogenesis
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Nature Communications. 2016, roč. 7, Jul, p. 12061
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IF = 12.124
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doi
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Harrall, K. K. - Kechris, K. J. - Tabakoff, B. - Hoffman, P.L. - Hines, L. M. - Tsukamoto, H. - Pravenec, Michal - Printz, M. - Saba, L. M.
Uncovering the liver’s role in immunity through RNA co-expression networks
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Mammalian Genome. 2016, roč. 27, 9-10, p. 469-484
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IF = 2.509
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doi
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Kurtz, T. W. - DiCarlo, S. E. - Pravenec, Michal - Schmidlin, O. - Tanaka, M. - Morris Jr., R. C.
An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension
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Kidney International. 2016, roč. 90, 5, p. 965-973
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IF = 7.916
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doi
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Manakov, D. - Ujčíková, Hana - Pravenec, Michal - Novotný, J.
Alterations in the cardiac proteome of the spontaneously hypertensive rat induced by transgenic expression of CD36
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Journal of Proteomics. 2016, roč. 145, Aug 11, p. 177-186
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IF = 3.914
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doi
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Pravenec, Michal - Kožich, V. - Krijt, J. - Sokolová, J. - Zídek, Václav - Landa, Vladimír - Mlejnek, Petr - Šilhavý, Jan - Šimáková, Miroslava - Škop, V. - Trnovská, J. - Kazdová, L. - Kajiya, T. - Wang, J. M. - Kurtz, T. W.
Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome
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Hypertension. 2016, roč. 67, 2, p. 335-341
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IF = 6.857
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[
doi
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Myška, A. - Száková, J. - Fučíková, A. - Mlejnek, Petr - Zídek, Václav - Tremlová, J. - Mestek, O. - Koplík, R. - Zídková, J. - Melčová, M. - Tlustoš, P.
Effect of selenium-enriched defatted rape seeds on tissue cadmium and essential elements utilization in rats
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Czech Journal of Animal Science. 2016, roč. 61, 11, p. 496-505
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IF = 0.741
[ASEP]
Šilhavý, Jan - Zídek, Václav - Landa, Vladimír - Šimáková, Miroslava - Mlejnek, Petr - Oliyarnyk, O. - Malínská, H. - Kazdová, L. - Mancini, M. - Pravenec, Michal
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Rosuvastatin ameliorates inflammation, renal fat accumulation, and kidney injury in transgenic spontaneously hypertensive rats expressing human C-reactive protein
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Physiological Research. 2015, Vol. 64, 3, p. 295-301
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IF = 1.618
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Trnovská, J. - Šilhavý, Jan - Zídek, Václav - Šimáková, Miroslava - Mlejnek, Petr - Landa, Vladimír - Eigner, Sebastian - Eigner-Henke, Kateřina - Škop, V. - Oliyarnyk, O. - Kazdová, L. - Mráček, Tomáš - Houštěk, Josef - Pravenec, Michal
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Gender-related effects on substrate utilization and metabolic adaptation in hairless spontaneously hypertensive rat
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Physiological Research. 2015, Vol. 64, 1, p. 51-60
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IF = 1.618
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Schafer, S. - Adami, E. - Heinig, M. - Rodrigues, K. E. C. - Kreuchwig, F. - Šilhavý, Jan - van Heesch, S. - Simaite, D. - Rajewsky, N. - Cuppen, E. - Pravenec, Michal - Vingron, M. - Cook, S. A. - Hubner, N.
Translational regulation shapes the molecular landscape of complex disease phenotypes
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Nature Communications. 2015, Vol. 6, -, p. 7200
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IF = 11.329
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doi
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Kurtz, T. W. - Dominiczak, A. F. - DiCarlo, S. E. - Pravenec, Michal - Morris Jr., R. C.
Molecular-Based Mechanisms of Mendelian Forms of Salt-Dependent Hypertension Questioning the Prevailing Theory
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Hypertension. 2015, Vol. 65, 5, p. 932-941
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IF = 6.294
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doi
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Heinig, M. - Colomé-Tatché, M. - Taudt, A. - Rintisch, C. - Schafer, S. - Pravenec, Michal - Hubner, N. - Vingron, M. - Johannes, F.
histoneHMM: Differential analysis of histone modifications with broad genomic footprints
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B M C Bioinformatics. 2015, Vol. 16, Feb 22, p. 60
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IF = 2.435
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doi
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Zicha, Josef - Dobešová, Zdenka - Zídek, Václav - Šilhavý, Jan - Šimáková, Miroslava - Mlejnek, Petr - Vaněčková, Ivana - Kuneš, Jaroslav - Pravenec, Michal
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Pharmacogenetic Analysis of Captopril Effects on Blood Pressure: Possible Role of the Ednrb (Endothelin Receptor Type B) Candidate Gene
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Physiological Research 2014, roč. 63, 2, p. 263-265. ISSN 0862-8408.
IF = 1.293
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Zídková, J. - Melčová, M. - Bartošová, K. - Šestáková, Ivana - Zídek, Václav - Száková, J. - Miholová, D. - Tlustoš, P.
Impact of cadmium on the level of hepatic metallothioneins, essential elements, and selected enzymes in the experimental rat model
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Czech Journal of Animal Science. 2014, roč. 59, 12, p. 548-556. ISSN 1212-1819.
IF = 1.183
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Vlčková, V. - Malinová, M. - Koubková, B. - Szaková, J. - Zídek, Václav - Fučíková, A. - Zídková, J. - Kolihová, D. - Tlustoš, P.
Long-term effect of diet amended by risk elements contaminated soils on risk element penetration and physiological parameters of rats
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Czech Journal of Animal Science. 2014, roč. 59, 9, p. 416-427. ISSN 1212-1819.
IF = 1.183
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Šilhavý, Jan - Zídek, Václav - Mlejnek, Petr - Landa, Vladimír - Šimáková, Miroslava - Strnad, Hynek - Oliyarnyk, O. - Škop, V. - Kazdová, L. - Kurtz, T. - Pravenec, Michal
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Fumaric Acid Esters Can Block Pro-Inflammatory Actions of Human CRP and Ameliorate Metabolic Disturbances in Transgenic Spontaneously Hypertensive Rats
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PLoS ONE 2014, roč. 9, 7, e101906. ISSN 1932-6203.
IF = 3.234
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doi
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Šilhavý, Jan - Zídek, Václav - Landa, Vladimír - Šimáková, Miroslava - Mlejnek, Petr - Škop, V. - Oliyarnyk, O. - Kazdová, L. - Mancini, M. - Saar, K. - Schulz, H. - Hübner, N. - Kurtz, T. W. - Pravenec, Michal
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Rosuvastatin Can Block Pro-Inflammatory Actions of Transgenic Human C-Reactive Protein Without Reducing its Circulating Levels
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Cardiovascular Therapeutics 2014, roč. 32, 2, p. 59-65. ISSN 1755-5914.
IF = 2.362
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doi
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Rintisch, C. - Heinig, M. - Bauerfeind, A. - Schafer, S. - Mieth, Ch. - Patone, G. - Hummel, O. - Chen, W. - Cook, S. - Cuppen, E. - Colomé-Tatché, M. - Johannes, F. - Jansen, R. C. - Neil, H. - Werner, M. - Pravenec, Michal - Vingron, M. - Hubner, N.
Natural variation of histone modification and its impact on gene expression in the rat genome
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Genome Research 2014, roč. 24, jun, p. 942-953. ISSN 1088-9051.
IF = 14.63
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[
doi
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Pravenec, Michal - Křen, Vladimír - Landa, Vladimír - Mlejnek, Petr - Musilová, Alena - Šilhavý, Jan - Šimáková, Miroslava - Zídek, Václav
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Recent progress in the genetics of spontaneously hypertensive rats
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Physiological Research 2014, roč. 63, suppl.1, s1-s8. ISSN 0862-8408.
IF = 1.293
[ASEP]
Liška, F. - Mancini, M. - Krupková, M. - Chylíková, B. - Křenová, D. - Šeda, O. - Šilhavý, Jan - Mlejnek, Petr - Landa, Vladimír - Zídek, Václav - d´Amati, G. - Pravenec, Michal - Křen, Vladimír
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Plzf as a Candidate Gene Predisposing the Spontaneously Hypertensive Rat to Hypertension, Left Ventricular Hypertrophy, and Interstitial Fibrosis
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American Journal of Hypertension 2014, roč. 27, 1, p. 99-106. ISSN 0895-7061.
IF = 2.852
[ASEP]
[
doi
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Landa, Vladimír - Zídek, Václav - Mlejnek, Petr - Šimáková, Miroslava - Šilhavý, Jan - Trnovská, J. - Kazdová, L. - Pravenec, Michal
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Sterol regulatory element binding protein 2 overexpression is associated with reduced adipogenesis and ectopic fat accumulation in transgenic spontaneously hypertensive rats
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Physiological Research. 2014, roč. 63, 5, p. 587-590
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IF = 1.293
[ASEP]
Johnson, M.D. - Mueller, M. - Adamowicz-Brice, M. - Collins, M. J. - Gellert, P. - Maratou, K. - Srivastava, P. K. - Rotival, M. - Butt, S. - Game, L. - Atanur, S. S. - Silver, N. - Norsworthy, P. J. - Langley, S. R. - Petretto, E. - Pravenec, Michal - Aitman, T. J.
Genetic Analysis of the Cardiac Methylome at Single Nucleotide Resolution in a Model of Human Cardiovascular Disease
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PLoS Genetics. 2014, roč. 10, 12, e1004813. ISSN 1553-7390.
IF = 7.528
[ASEP]
[
doi
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Ivics, Z. - Mátés, L. - Yau, T. Y. - Landa, Vladimír - Zídek, Václav - Bashir, S. - Hoffmann, O. I. - Hiripi, L. - Garrels, W. - Kues, W. A. - Bösze, Z. - Geurts, A. - Pravenec, Michal - Rülicke, T. - Izsvák, Z.
Germline transgenesis in rodents by pronuclear microinjection of Sleeping Beauty transposons
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Nature Protocols 2014, roč. 9, 4, p. 773-793. ISSN 1754-2189.
IF = 9.673
[ASEP]
[
doi
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Ivics, Z. - Hiripi, L. - Hoffmann, O. I. - Mátés, L. - Yau, T. Y. - Bashir, S. - Zídek, Václav - Landa, Vladimír - Geurts, A. - Pravenec, Michal - Rülicke, T. - Bösze, Z. - Izsvák, Z.
Germline transgenesis in rabbits by pronuclear microinjection of Sleeping Beauty transposons
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Nature Protocols 2014, roč. 9, 4, p. 794-809. ISSN 1754-2189.
IF = 9.673
[ASEP]
[
doi
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Ivics, Z. - Garrels, W. - Mátés, L. - Yau, T. Y. - Bashir, S. - Zídek, Václav - Landa, Vladimír - Geurts, A. - Pravenec, Michal - Rülicke, T. - Kues, W. A. - Izsvák, Z.
Germline transgenesis in pigs by cytoplasmic microinjection of Sleeping Beauty transposons
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Nature Protocols 2014, roč. 9, 4, p. 810-827. ISSN 1754-2189.
IF = 9.673
[ASEP]
[
doi
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Houštěk, Josef - Vrbacký, Marek - Hejzlarová, Kateřina - Zídek, Václav - Landa, Vladimír - Šilhavý, Jan - Šimáková, Miroslava - Mlejnek, Petr - Kazdová, L. - Mikšík, Ivan - Neckář, Jan - Papoušek, František - Kolář, František - Kurtz, T. W. - Pravenec, Michal
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Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction
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Physiological Genomics 2014, roč. 46, 18, p. 671-678. ISSN 1094-8341.
IF = 2.374
[ASEP]
[
doi
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Zídek, Václav - Mlejnek, Petr - Šimáková, Miroslava - Šilhavý, Jan - Landa, Vladimír - Kazdová, L. - Pravenec, Michal - Kurtz, T. W.
Tissue-Specific Peroxisome Proliferator Activated Receptor Gamma Expression and Metabolic Effects of Telmisartan
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American Journal of Hypertension, 2013, Vol. 26, 6, p. 829-835
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IF = 3.665
[ASEP]
[
doi
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Pravenec, Michal - Kožich, V. - Krijt, J. - Sokolová, J. - Zídek, Václav - Landa, Vladimír - Šimáková, Miroslava - Mlejnek, Petr - Šilhavý, Jan - Oliyarnyk, O. - Kazdová, L. - Kurtz, T. W.
Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure, and Insulin Resistance in Spontaneously Hypertensive Rats
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American Journal of Hypertension, 2013, Vol. 26, 1, p. 135-140
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IF = 3.665
[ASEP]
[
doi
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Mancini, M. - Petretto, E. - Kleinert, C. - Scavone, A. - De, T. - Cook, S. - Šilhavý, Jan - Zídek, Václav - Pravenec, Michal - d´Amati, G. - Camici, P.G.
Mapping genetic determinants of coronary microvascular remodeling in the spontaneously hypertensive rat
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Basic Research in Cardiology, 2013, Vol. 108, 1, p. 316
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IF = 5.904
[ASEP]
[
doi
]
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