1. Plzf as a Candidate Gene Predisposing the Spontaneously Hypertensive Rat to Hypertension, Left Ventricular Hypertrophy, and Interstitial Fibrosis
- Author
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Petr Mlejnek, Michaela Krupková, Jan Šilhavý, František Liška, Michal Pravenec, Giulia d' Amati, Drahomíra Křenová, Vladimír Landa, Vladimír Křen, Ondřej Šeda, Massimiliano Mancini, Blanka Chylíková, and Vaclav Zidek
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Cardiac fibrosis ,Quantitative Trait Loci ,Congenic ,Essential hypertension ,Left ventricular hypertrophy ,Muscle hypertrophy ,Spontaneously hypertensive rat ,Animals, Congenic ,Fibrosis ,Rats, Inbred SHR ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Genetic Predisposition to Disease ,Promyelocytic Leukemia Zinc Finger Protein ,cardiovascular diseases ,Genetic Association Studies ,business.industry ,Myocardium ,Hemodynamics ,medicine.disease ,Rats ,DNA-Binding Proteins ,Disease Models, Animal ,spontaneously hypertensive rat ,blood pressure ,hypertension ,left ventricular hypertrophy ,quantitative trait locus ,myocardial interstitial fibrosis ,plzf (promyelocytic leukemia zinc finger) gene ,Phenotype ,Endocrinology ,Gene Expression Regulation ,Hypertension ,Hypertrophy, Left Ventricular ,Myocardial fibrosis ,business - Abstract
BACKGROUND The spontaneously hypertensive rat (SHR) is the most widely used model of essential hypertension and is susceptible to left ventricular hypertrophy (LVH) and myocardial fibrosis. Recently, a quantitative trait locus (QTL) that influences heart interstitial fibrosis was mapped to chromosome 8. Our aim was to dissect the genetic basis of this QTL(s) predisposing SHR to hypertension, LVH, and interstitial fibrosis. METHODS Hemodynamic and histomorphometric analyses were performed in genetically defined SHR.PD-chr.8 minimal congenic strain (PD5 subline) rats. RESULTS The differential segment, genetically isolated within the PD5 subline, spans 788kb and contains 7 genes, including the promyelocytic leukemia zinc finger (Plzf) gene that has been implicated in hypertrophy and cardiac fibrosis. Mutant Plzf allele contains a 2,964-bp deletion in intron 2. The PD5 congenic strain, when compared with the SHR, showed significantly reduced systolic blood pressure by approximately 15mm Hg (P = 0.002), amelioration of LVH (0.23±0.02 vs. 0.39±0.02g/100g body weight; P < 0.00001), and reduced interstitial fibrosis (17,478±1,035 vs. 41,530±3,499 μm(2); P < 0.0001). The extent of amelioration of LVH and interstitial fibrosis was disproportionate to blood pressure decrease in congenic rats, suggesting an important role for genetic factors. Cardiac expression of Plzf was significantly reduced in prehypertensive (8 and 21 days) congenic animals compared with controls. CONCLUSIONS These results provide compelling evidence of a significant role for genetic factors in regulating blood pressure, LVH, and cardiac fibrosis and identify mutant Plzf as a prominent candidate gene.
- Published
- 2014
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