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Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat

Liška, František
Author Liška, František From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Landa, Vladimír
Author Landa, Vladimír From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Zídek, Václav
Author Zídek, Václav From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Mlejnek, Petr
Author Mlejnek, Petr From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Šilhavý, Jan
Author Šilhavý, Jan From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Šimáková, Miroslava
Author Šimáková, Miroslava From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Strnad, Hynek
Author Strnad, Hynek From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Trnovská, Jaroslava
Author Trnovská, Jaroslava From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Škop, Vojtěch
Author Škop, Vojtěch From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Kazdová, Ludmila
Author Kazdová, Ludmila From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Starker, Colby G
Author Starker, Colby G From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Voytas, Daniel F
Author Voytas, Daniel F From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Izsvák, Zsuzsanna
Author Izsvák, Zsuzsanna From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Mancini, Massimiliano
Author Mancini, Massimiliano From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Šeda, Ondřej
Author Šeda, Ondřej From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Křen, Vladimír
Author Křen, Vladimír From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.)
Pravenec, Michal
Author Pravenec, Michal From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic (F.L., O.Š., V.K., M.P.); Institute of Physiology (V.L., V.Z., P.M., J.Š., M.Š., M.P.) and Institute of Molecular Genetics (H.S.), Czech Academy of Sciences, Prague, Czech Republic; Institute for Experimental Medicine, Prague, Czech Republic (J.T., V.Š., L.K.); Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis (C.G.S., D.F.V.); Max-Delbrück-Center for Molecular Medicine in the Hemholtz Society, Berlin, Germany (Z.I.); and Department of Molecular Medicine "Sapienza" University of Rome, Italy (M.M.). pravenec@biomed.cas.cz

Hypertension (Dallas, Tex.. 2017 Jun ; 69 (6) : 1084-1091. [epub] 20170410

Hypertension
ISSN 1524-4563 | 0194-911X
Source

Language English Country United States Media print-electronic

Document type Journal Article

Persistent link https://www.medvik.cz/link/pmid28396530

PubMed 28396530
DOI 10.1161/hypertensionaha.116.08798
PII: HYPERTENSIONAHA.116.08798
Knihovny.cz E-resources

Keywords
fibrosis, hypertension, hypertrophy, left ventricular, rats, inbred SHR, transcriptome,
MeSH
Alleles MeSH
Analysis of Variance MeSH
Down-Regulation MeSH
Essential Hypertension MeSH
Phenotype MeSH
Fibrosis genetics MeSH
Hypertension genetics pathology MeSH
Hypertrophy, Left Ventricular genetics physiopathology MeSH
Myocytes, Cardiac metabolism MeSH
Rats MeSH
Cells, Cultured MeSH
Real-Time Polymerase Chain Reaction methods MeSH
Quantitative Trait Loci MeSH
Blood Pressure Determination MeSH
Lipid Metabolism genetics MeSH
Rats, Inbred SHR MeSH
Promyelocytic Leukemia Zinc Finger Protein MeSH
Gene Expression Profiling * MeSH
Kruppel-Like Transcription Factors genetics MeSH
Blotting, Western MeSH
Animals MeSH
Check Tag
Rats MeSH
Male MeSH
Animals MeSH
Publication type
Journal Article MeSH
Names of Substances
Promyelocytic Leukemia Zinc Finger Protein MeSH
Kruppel-Like Transcription Factors MeSH
Zbtb16 protein, mouse MeSH Browser

The spontaneously hypertensive rat (SHR), one of the most widely used model of essential hypertension, is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, quantitative trait loci influencing blood pressure, left ventricular mass, and heart interstitial fibrosis were genetically isolated within a minimal congenic subline that contains only 7 genes, including mutant Plzf (promyelocytic leukemia zinc finger) candidate gene. To identify Plzf as a quantitative trait gene, we targeted Plzf in the SHR using the transcription activator-like effector nuclease technique and obtained SHR line harboring targeted Plzf gene with a premature stop codon. Because the Plzf targeted allele is semilethal, morphologically normal heterozygous rats were used for metabolic and hemodynamic analyses. SHR-Plzf+/- heterozygotes versus SHR wild-type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol, and better glucose tolerance. In addition, SHR-Plzf+/- rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared with wild-type controls. Blood pressure was comparable in SHR versus SHR-Plzf+/-; however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf+/- rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes that play a role in metabolic pathways, PPAR (peroxisome proliferator-activated receptor) signaling, and cell cycle regulation. These results provide evidence for an important role of Plzf in regulation of metabolic and cardiac traits in the rat and suggest a cross talk between cell cycle regulators, metabolism, cardiac hypertrophy, and fibrosis.

From the Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

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