title: Downregulation ofPlzfGene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat.
abstract: 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 mutantPlzf(promyelocytic leukemia zinc finger) candidate gene. To identifyPlzfas a quantitative trait gene, we targetedPlzfin the SHR using the transcription activator-like effector nuclease technique and obtained SHR line harboring targetedPlzfgene with a premature stop codon. Because thePlzftargeted 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 ofPlzfin regulation of metabolic and cardiac traits in the rat and suggest a cross talk between cell cycle regulators, metabolism, cardiac hypertrophy, and fibrosis.
authors.affiliation: 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.).
authors.forename: František
authors.initials: F
authors.lastname: Liška
authors.affiliation: 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.).
authors.forename: Vladimír
authors.initials: V
authors.lastname: Landa
authors.affiliation: 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.).
authors.forename: Václav
authors.initials: V
authors.lastname: Zídek
authors.affiliation: 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.).
authors.forename: Petr
authors.initials: P
authors.lastname: Mlejnek
authors.affiliation: 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.).
authors.forename: Jan
authors.initials: J
authors.lastname: Šilhavý
authors.affiliation: 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.).
authors.forename: Miroslava
authors.initials: M
authors.lastname: Šimáková
authors.affiliation: 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.).
authors.forename: Hynek
authors.initials: H
authors.lastname: Strnad
authors.affiliation: 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.).
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Trnovská
authors.affiliation: 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.).
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Škop
authors.affiliation: 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.).
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kazdová
authors.affiliation: 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.).
authors.forename: Colby G
authors.initials: CG
authors.lastname: Starker
authors.affiliation: 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.).
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Voytas
authors.affiliation: 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.).
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Izsvák
authors.affiliation: 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.).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mancini
authors.affiliation: 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.).
authors.forename: Ondřej
authors.initials: O
authors.lastname: Šeda
authors.affiliation: 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.).
authors.forename: Vladimír
authors.initials: V
authors.lastname: Křen
authors.affiliation: 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.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
mesh_terms: D000483:Alleles; D000704:Analysis of Variance; D000818:Animals; D001795:Blood Pressure Determination; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation; D000075222:Essential Hypertension; D005355:Fibrosis / Q000235:genetics; D020869:Gene Expression Profiling; D006973:Hypertension / Q000235:genetics* / Q000473:pathology*; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
chemical_list: D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse
keywords: fibrosis; hypertension; hypertrophy, left ventricular; rats, inbred SHR; transcriptome