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Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat
F. Liška, V. Landa, V. Zídek, P. Mlejnek, J. Šilhavý, M. Šimáková, H. Strnad, J. Trnovská, V. Škop, L. Kazdová, CG. Starker, DF. Voytas, Z. Izsvák, M. Mancini, O. Šeda, V. Křen, M. Pravenec,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
NLK
Free Medical Journals
od 1979 do Před 1 rokem
Open Access Digital Library
od 1979-01-01
Open Access Digital Library
od 1979-01-01
- MeSH
- alely MeSH
- analýza rozptylu MeSH
- down regulace MeSH
- fenotyp MeSH
- fibróza genetika MeSH
- hypertenze genetika patologie MeSH
- hypertrofie levé komory srdeční genetika patofyziologie MeSH
- kardiomyocyty metabolismus MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- kvantitativní polymerázová řetězová reakce metody MeSH
- lokus kvantitativního znaku MeSH
- měření krevního tlaku MeSH
- metabolismus lipidů genetika MeSH
- potkani inbrední SHR MeSH
- stanovení celkové genové exprese * MeSH
- transkripční faktory Krüppel-like genetika MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
Department of Molecular Medicine Sapienza University of Rome Italy
Institute for Experimental Medicine Prague Czech Republic
Institute of Molecular Genetics Czech Academy of Sciences Prague Czech Republic
Institute of Physiology Czech Academy of Sciences Prague Czech Republic
Max Delbrück Center for Molecular Medicine in the Hemholtz Society Berlin Germany
Citace poskytuje Crossref.org
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- $a Liška, František $u From the Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
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- $a 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.
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