TY - JOUR
T1 - Downregulation of Plzf Gene Ameliorates Metabolic and Cardiac Traits in the Spontaneously Hypertensive Rat
AU - Liška, František
AU - Landa, Vladimír
AU - Zídek, Václav
AU - Mlejnek, Petr
AU - Šilhavý, Jan
AU - Šimáková, Miroslava
AU - Strnad, Hynek
AU - Trnovská, Jaroslava
AU - Škop, Vojtěch
AU - Kazdová, Ludmila
AU - Starker, Colby G.
AU - Voytas, Daniel F.
AU - Izsvák, Zsuzsanna
AU - Mancini, Massimiliano
AU - Šeda, Ondřej
AU - Křen, Vladimír
AU - Pravenec, Michal
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - fibrosis
KW - hypertension
KW - hypertrophy, left ventricular
KW - rats, inbred SHR
KW - transcriptome
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U2 - 10.1161/HYPERTENSIONAHA.116.08798
DO - 10.1161/HYPERTENSIONAHA.116.08798
M3 - Article
C2 - 28396530
AN - SCOPUS:85017450596
SN - 0194-911X
VL - 69
SP - 1084
EP - 1091
JO - Hypertension
JF - Hypertension
IS - 6
ER -