Downregulation of Plzf Gene 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 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…
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Several genes were previously connected with fatty liver disease such as Nr3c1, Nr3c2, Zbtb16, Dnmt1, and Keap1, but most of the top genes had no connections with liver disease or NASH.
“Several genes were previously connected with fatty liver disease such as the glucocorticoid receptor Nr3c128,29, the mineralocorticoid receptor Nr3c230,31, the transcription factor Zbtb1632, the DNA methyltransferase Dnmt133, and the E3 ubiquitin ligase adaptor Keap134,35, but most of the top genes had no connections with liver disease or NASH.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [32]
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Wang, Z., Zhu, S., Jia, Y., Wang, Y., Kubota, N., Fujiwara, N., Gordillo, R., Lewis, C., Zhu, M., Sharma, T., et al. (2023) · Cell · doi:10.1016/j.cell.2023.03.014 · Cited by 72 · see citing works
Mineralocorticoid receptor promotes cardiac macrophage inflammaging
Fraccarollo, D., Geffers, R., Galuppo, P., & Bauersachs, J. (2024) · Basic Research in Cardiology · doi:10.1007/s00395-024-01032-6 · Cited by 32 · see citing works
- Authors
- Liška, F., Landa, V., Zídek, V., Mlejnek, P., Šilhavý, J., Šimáková, M., Strnad, H., Trnovská, J., Škop, V., Kazdová, L., Starker, C. G., Voytas, D. F., Izsvák, Z., Mancini, M., Šeda, O., Křen, V., & Pravenec, M.
- Affiliations
- University of Minnesota (US)
- 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,...
- ORCID
- Venue
- Hypertension
- Published
- 2017-06
- Volume
- 69
- Issue
- 6
- Pages
- 1084-1091
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2605742670
- Cited by
- 42
- References
- 0
- Citations by year
- 2025: 8 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- PLZF, spontaneously hypertensive rats, essential hypertension, left ventricular hypertrophy, myocardial fibrosis, insulin sensitivity, glucose tolerance, lipid metabolism, PPAR signaling, cell cycle regulation, quantitative trait loci, congenic rats
- MeSH terms
- Essential Hypertension, Promyelocytic Leukemia Zinc Finger Protein, Alleles, Analysis of Variance, Animals, Blood Pressure Determination, Cells, Cultured, Fibrosis, Hypertension, Male, Phenotype, Rats, Inbred SHR, Blotting, Western, Down-Regulation, Hypertrophy, Left Ventricular, Gene Expression Profiling, Myocytes, Cardiac, Quantitative Trait Loci, Lipid Metabolism, Rats, Kruppel-Like Transcription Factors, Real-Time Polymerase Chain Reaction
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