16 results on '"Vladimír Landa"'
Search Results
2. Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls.
- Author
-
Jaroslava Trnovská, Jan Šilhavý, Ondřej Kuda, Vladimír Landa, Václav Zídek, Petr Mlejnek, Miroslava Šimáková, Hynek Strnad, Vojtěch Škop, Olena Oliyarnyk, Ludmila Kazdová, Martin Haluzík, and Michal Pravenec
- Subjects
Medicine ,Science - Abstract
Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
- Published
- 2017
- Full Text
- View/download PDF
3. Targeting of the Plzf Gene in the Rat by Transcription Activator-Like Effector Nuclease Results in Caudal Regression Syndrome in Spontaneously Hypertensive Rats.
- Author
-
František Liška, Renata Peterková, Miroslav Peterka, Vladimír Landa, Václav Zídek, Petr Mlejnek, Jan Šilhavý, Miroslava Šimáková, Vladimír Křen, Colby G Starker, Daniel F Voytas, Zsuzsanna Izsvák, and Michal Pravenec
- Subjects
Medicine ,Science - Abstract
Recently, it has been found that spontaneous mutation Lx (polydactyly-luxate syndrome) in the rat is determined by deletion of a conserved intronic sequence of the Plzf (Promyelocytic leukemia zinc finger protein) gene. In addition, Plzf is a prominent candidate gene for quantitative trait loci (QTLs) associated with cardiac hypertrophy and fibrosis in the spontaneously hypertensive rat (SHR). In the current study, we tested the effects of Plzf gene targeting in the SHR using TALENs (transcription activator-like effector nucleases). SHR ova were microinjected with constructs pTAL438/439 coding for a sequence-specific endonuclease that binds to target sequence in the first coding exon of the Plzf gene. Out of 43 animals born after microinjection, we detected a single male founder. Sequence analysis revealed a deletion of G that resulted in frame shift mutation starting in codon 31 and causing a premature stop codon at position of amino acid 58. The Plzftm1Ipcv allele is semi-lethal since approximately 95% of newborn homozygous animals died perinatally. All homozygous animals exhibited manifestations of a caudal regression syndrome including tail anomalies and serious size reduction and deformities of long bones, and oligo- or polydactyly on the hindlimbs. The heterozygous animals only exhibited the tail anomalies. Impaired development of the urinary tract was also revealed: one homozygous and one heterozygous rat exhibited a vesico-ureteric reflux with enormous dilatation of ureters and renal pelvis. In the homozygote, this was combined with a hypoplastic kidney. These results provide evidence for the important role of Plzf gene during development of the caudal part of a body-column vertebrae, hindlimbs and urinary system in the rat.
- Published
- 2016
- Full Text
- View/download PDF
4. Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein.
- Author
-
Hana Malínská, Olena Oliyarnyk, Vojtěch Škop, Jan Šilhavý, Vladimír Landa, Václav Zídek, Petr Mlejnek, Miroslava Šimáková, Hynek Strnad, Ludmila Kazdová, and Michal Pravenec
- Subjects
Medicine ,Science - Abstract
Inflammation and oxidative and dicarbonyl stress play important roles in the pathogenesis of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver. However, its "pleiotropic" effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 8-month-old male transgenic SHR-CRP rats with metformin (5 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without metformin. In a similar fashion, we studied a group of nontransgenic SHR treated with metformin and an untreated group of nontransgenic SHR controls. In each group, we studied 6 animals. Parameters of glucose and lipid metabolism and oxidative and dicarbonyl stress were measured using standard methods. Gene expression profiles were determined using Affymetrix GeneChip Arrays. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL-6, TNFα and MCP-1 while levels of human CRP remained unchanged. Metformin significantly reduced oxidative stress (levels of conjugated dienes and TBARS) and dicarbonyl stress (levels of methylglyoxal) in left ventricles, but not in kidneys. No significant effects of metformin on oxidative and dicarbonyl stress were observed in SHR controls. In addition, metformin treatment reduced adipose tissue lipolysis associated with human CRP. Possible molecular mechanisms of metformin action-studied by gene expression profiling in the liver-revealed deregulated genes from inflammatory and insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP, metformin protects against inflammation and oxidative and dicarbonyl stress in the heart, but not in the kidney. Accordingly, these cardioprotective effects of metformin might be especially effective in diabetic patients with high levels of CRP.
- Published
- 2016
- Full Text
- View/download PDF
5. Embryogenesis of Aphidoletes aphidimyza (Diptera: Cecidomyiidae): Morphological markers for staging of living embryos
- Author
-
Jan HAVELKA and Vladimír LANDA
- Subjects
cecidomyiidae ,aphidoletes aphidimyza ,biological control ,aphids ,insect embryogenesis ,embryonic markers ,cryopreservation of eggs ,entomophagous insects ,Zoology ,QL1-991 - Abstract
Determination of embryonic stages is an important prerequisite for the long-term cryopreservation of eggs and embryos of the predatory gall midge Aphidoletes aphidimyza. This paper describes the embryonic development of this insect based on light microscopy. Gall midge embryogenesis lasts, on average, 102 h at 17°C and 144 h at 15°C. Living embryos can be quickly separated into ten stages that are clearly defined by specific morphological markers. The necessity for selecting definite embryonic stages for cryobiological storage is discussed.
- Published
- 2007
- Full Text
- View/download PDF
6. Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats.
- Author
-
Jan Šilhavý, Václav Zídek, Petr Mlejnek, Vladimír Landa, Miroslava Šimáková, Hynek Strnad, Olena Oliyarnyk, Vojtěch Škop, Ludmila Kazdová, Theodore Kurtz, and Michal Pravenec
- Subjects
Medicine ,Science - Abstract
Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.
- Published
- 2014
- Full Text
- View/download PDF
7. Correction: Targeting of the Plzf Gene in the Rat by Transcription Activator-Like Effector Nuclease Results in Caudal Regression Syndrome in Spontaneously Hypertensive Rats
- Author
-
Renata Peterkova, Zsuzsanna Izsvák, Vladimír Landa, Vladimír Křen, Miroslava Šimáková, Michal Pravenec, Colby G. Starker, Daniel F. Voytas, František Liška, Jan Šilhavý, Petr Mlejnek, Miroslav Peterka, and Vaclav Zidek
- Subjects
Male ,Tail ,Heterozygote ,Genotype ,Science ,Quantitative Trait Loci ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Rats, Inbred SHR ,Transcription Activator-Like Effector Nucleases ,medicine ,Animals ,Abnormalities, Multiple ,Promyelocytic Leukemia Zinc Finger Protein ,Amino Acid Sequence ,Frameshift Mutation ,Gene ,Alleles ,030304 developmental biology ,0303 health sciences ,Transcription activator-like effector nuclease ,Multidisciplinary ,Caudal regression syndrome ,Base Sequence ,Homozygote ,Correction ,Exons ,medicine.disease ,Molecular biology ,Rats ,DNA-Binding Proteins ,Polydactyly ,Gene Targeting ,Medicine ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Recently, it has been found that spontaneous mutation Lx (polydactyly-luxate syndrome) in the rat is determined by deletion of a conserved intronic sequence of the Plzf (Promyelocytic leukemia zinc finger protein) gene. In addition, Plzf is a prominent candidate gene for quantitative trait loci (QTLs) associated with cardiac hypertrophy and fibrosis in the spontaneously hypertensive rat (SHR). In the current study, we tested the effects of Plzf gene targeting in the SHR using TALENs (transcription activator-like effector nucleases). SHR ova were microinjected with constructs pTAL438/439 coding for a sequence-specific endonuclease that binds to target sequence in the first coding exon of the Plzf gene. Out of 43 animals born after microinjection, we detected a single male founder. Sequence analysis revealed a deletion of G that resulted in frame shift mutation starting in codon 31 and causing a premature stop codon at position of amino acid 58. The Plzftm1Ipcv allele is semi-lethal since approximately 95% of newborn homozygous animals died perinatally. All homozygous animals exhibited manifestations of a caudal regression syndrome including tail anomalies and serious size reduction and deformities of long bones, and oligo- or polydactyly on the hindlimbs. The heterozygous animals only exhibited the tail anomalies. Impaired development of the urinary tract was also revealed: one homozygous and one heterozygous rat exhibited a vesico-ureteric reflux with enormous dilatation of ureters and renal pelvis. In the homozygote, this was combined with a hypoplastic kidney. These results provide evidence for the important role of Plzf gene during development of the caudal part of a body-column vertebrae, hindlimbs and urinary system in the rat.
- Published
- 2020
8. Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls
- Author
-
Michal Pravenec, Hynek Strnad, V. Škop, Jan Šilhavý, Jaroslava Trnovska, Petr Mlejnek, Miroslava Šimáková, Vaclav Zidek, Olena Oliyarnyk, Ludmila Kazdova, Ondřej Kuda, Vladimír Landa, and Martin Haluzik
- Subjects
0301 basic medicine ,Physiology ,medicine.medical_treatment ,lcsh:Medicine ,Gene Expression ,Fatty Acids, Nonesterified ,Pathology and Laboratory Medicine ,Biochemistry ,Animals, Genetically Modified ,Endocrinology ,Adipose Tissue, Brown ,Brown adipose tissue ,Salsalate ,Medicine and Health Sciences ,Insulin ,lcsh:Science ,Immune Response ,Metabolic Syndrome ,Multidisciplinary ,Chemistry ,Organic Compounds ,Monosaccharides ,Chemical Reactions ,Salicylates ,medicine.anatomical_structure ,C-Reactive Protein ,Adipose Tissue ,Liver ,Physical Sciences ,Hypertension ,Brown Adipose Tissue ,medicine.symptom ,Anatomy ,medicine.drug ,Research Article ,medicine.medical_specialty ,Immunology ,Carbohydrates ,Inflammation ,NLR Proteins ,03 medical and health sciences ,Insulin resistance ,Signs and Symptoms ,Lipid oxidation ,Diagnostic Medicine ,Internal medicine ,Oxidation ,medicine ,Genetics ,Animals ,Humans ,PPAR alpha ,Diabetic Endocrinology ,Endocrine Physiology ,Tumor Necrosis Factor-alpha ,lcsh:R ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Lipid metabolism ,Cell Biology ,medicine.disease ,Lipid Metabolism ,Hormones ,Rats ,Oxidative Stress ,030104 developmental biology ,Biological Tissue ,Glucose ,lcsh:Q ,Metabolic syndrome ,Insulin Resistance - Abstract
Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
- Published
- 2017
9. Plzf as a Candidate Gene Predisposing the Spontaneously Hypertensive Rat to Hypertension, Left Ventricular Hypertrophy, and Interstitial Fibrosis
- Author
-
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
- Full Text
- View/download PDF
10. Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure, and Insulin Resistance in Spontaneously Hypertensive Rats
- Author
-
Jan Šilhavý, Petr Mlejnek, Miroslava Šimáková, Jitka Sokolová, Viktor Kožich, Ludmila Kazdova, Olena Oliyarnyk, Theodore W. Kurtz, Michal Pravenec, Vaclav Zidek, Vladimír Landa, and Jakub Krijt
- Subjects
Male ,and promotion of well-being ,Homocysteine ,Blood Pressure ,030204 cardiovascular system & hematology ,Essential hypertension ,Cardiovascular ,folate deficiency ,chemistry.chemical_compound ,0302 clinical medicine ,Rats, Inbred SHR ,2.1 Biological and endogenous factors ,oxidative stress ,Aetiology ,2. Zero hunger ,Metabolic Syndrome ,0303 health sciences ,3. Good health ,Hypertension ,Original Article ,Hyperhomocysteinemia ,medicine.medical_specialty ,spontaneously hypertensive rat ,Inbred SHR ,hypertension ,Clinical Sciences ,Folic Acid Deficiency ,03 medical and health sciences ,Spontaneously hypertensive rat ,Insulin resistance ,Folic Acid ,Diabetes mellitus ,Internal medicine ,Glucose Intolerance ,Complementary and Integrative Health ,Internal Medicine ,medicine ,Animals ,3.3 Nutrition and chemoprevention ,Metabolic and endocrine ,030304 developmental biology ,Nutrition ,business.industry ,Prevention ,homocysteine ,medicine.disease ,Prevention of disease and conditions ,Rats ,Oxidative Stress ,B vitamins ,Endocrinology ,chemistry ,Cardiovascular System & Hematology ,ectopic fat accumulation ,Metabolic syndrome ,Insulin Resistance ,business - Abstract
BackgroundThe role of folate deficiency and associated hyperhomocysteinemia in the pathogenesis of metabolic syndrome is not fully established. In the current study, we analyzed the role of folate deficiency in pathogenesis of the metabolic syndrome in the spontaneously hypertensive rat (SHR).MethodsMetabolic and hemodynamic traits were assessed in SHR/Ola rats fed either folate-deficient or control diet for 4 weeks starting at the age of 3 months.ResultsCompared to SHRs fed a folate-replete diet, SHRs fed a folate-deficient diet showed significantly reduced serum folate (104 ± 5 vs. 11 ± 1 nmol/L, P < 0.0005) and urinary folate excretion (4.3 ± 0.6 vs. 1.2 ± 0.1 nmol/16 h, P < 0.0005) together with a near 3-fold increase in plasma total homocysteine concentration (4.5 ± 0.1 vs 13.1 ± 0.7 μmol/L, P < 0.0005), ectopic fat accumulation in liver, and impaired glucose tolerance. Folate deficiency also increased systolic blood pressure by approximately 15 mm Hg (P < 0.01). In addition, the low-folate diet was accompanied by significantly reduced activity of antioxidant enzymes and increased concentrations of lipoperoxidation products in liver, renal cortex, and heart.ConclusionsThese findings demonstrate that the SHR model is susceptible to the adverse metabolic and hemodynamic effects of low dietary intake of folate. The results are consistent with the hypothesis that folate deficiency can promote oxidative stress and multiple features of the metabolic syndrome that are associated with increased risk for diabetes and cardiovascular disease.
- Published
- 2013
- Full Text
- View/download PDF
11. Effects of Transgenic Expression of Dopamine Beta Hydroxylase (Dbh) Gene on Blood Pressure in Spontaneously Hypertensive Rats
- Author
-
Vladimír Landa, Vaclav Zidek, Michal Pravenec, Theodore W. Kurtz, Saiful A. Mir, Sucheta M. Vaingankar, Jan Šilhavý, Jiaming Wang, and Petr Mlejnek
- Subjects
medicine.medical_specialty ,DNA, Complementary ,Epinephrine ,Physiology ,Transgene ,Dopamine ,Blood Pressure ,Dopamine beta-Hydroxylase ,030204 cardiovascular system & hematology ,Biology ,Essential hypertension ,Left ventricular hypertrophy ,Article ,Gene Expression Regulation, Enzymologic ,Animals, Genetically Modified ,03 medical and health sciences ,Norepinephrine ,0302 clinical medicine ,Spontaneously hypertensive rat ,Internal medicine ,Rats, Inbred BN ,Rats, Inbred SHR ,Adrenal Glands ,medicine ,Animals ,Transgenes ,General Medicine ,medicine.disease ,Rats ,Endocrinology ,Blood pressure ,Hypertension ,030217 neurology & neurosurgery ,medicine.drug ,Brain Stem - Abstract
The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model.
- Published
- 2016
12. Targeting of the Plzf gene in the rat by transcription activator-like effector nuclease results in caudal regression syndrome in spontaneously hypertensive rats
- Author
-
Daniel F. Voytas, František Liška, Petr Mlejnek, Vladimír Landa, Michal Pravenec, Miroslav Peterka, Colby G. Starker, Zsuzsanna Izsvák, Vaclav Zidek, Renata Peterkova, Jan Šilhavý, Miroslava Šimáková, and Vladimír Křen
- Subjects
0301 basic medicine ,Candidate gene ,Embryology ,Vertebrae ,Physiology ,Science ,Biology ,Frameshift mutation ,Pelvis ,03 medical and health sciences ,Exon ,Spontaneously hypertensive rat ,medicine ,Medicine and Health Sciences ,Allele ,Animal Anatomy ,Gene ,Musculoskeletal System ,Genetics ,Tails ,Fetuses ,Multidisciplinary ,Caudal regression syndrome ,Body Weight ,Gene targeting ,Biology and Life Sciences ,Kidneys ,Renal System ,medicine.disease ,Molecular biology ,Spine ,030104 developmental biology ,Physiological Parameters ,Cardiovascular and Metabolic Diseases ,Medicine ,Anatomy ,Ureter ,Zoology ,Research Article ,Developmental Biology - Abstract
Recently, it has been found that spontaneous mutation Lx (polydactyly-luxate syndrome) in the rat is determined by deletion of a conserved intronic sequence of the Plzf (Promyelocytic leukemia zinc finger protein) gene. In addition, Plzf is a prominent candidate gene for quantitative trait loci (QTLs) associated with cardiac hypertrophy and fibrosis in the spontaneously hypertensive rat (SHR). In the current study, we tested the effects of Plzf gene targeting in the SHR using TALENs (transcription activator-like effector nucleases). SHR ova were microinjected with constructs pTAL438/439 coding for a sequence-specific endonuclease that binds to target sequence in the first coding exon of the Plzf gene. Out of 43 animals born after microinjection, we detected a single male founder. Sequence analysis revealed a deletion of G that resulted in frame shift mutation starting in codon 31 and causing a premature stop codon at position of amino acid 58. The Plzftm1Ipcv allele is semi-lethal since approximately 95% of newborn homozygous animals died perinatally. All homozygous animals exhibited manifestations of a caudal regression syndrome including tail anomalies and serious size reduction and deformities of long bones, and oligo- or polydactyly on the hindlimbs. The heterozygous animals only exhibited the tail anomalies. Impaired development of the urinary tract was also revealed: one homozygous and one heterozygous rat exhibited a vesico-ureteric reflux with enormous dilatation of ureters and renal pelvis. In the homozygote, this was combined with a hypoplastic kidney. These results provide evidence for the important role of Plzf gene during development of the caudal part of a body-column vertebrae, hindlimbs and urinary system in the rat.
- Published
- 2016
13. Fumaric Acid Esters Can Block Pro-Inflammatory Actions of Human CRP and Ameliorate Metabolic Disturbances in Transgenic Spontaneously Hypertensive Rats
- Author
-
Theodore W. Kurtz, Vaclav Zidek, V. Škop, Olena Oliyarnyk, Hynek Strnad, Petr Mlejnek, Miroslava Šimáková, Vladimír Landa, Ludmila Kazdova, Jan Šilhavý, and Michal Pravenec
- Subjects
Male ,Physiology ,Gene Transfer ,Anti-Inflammatory Agents ,lcsh:Medicine ,Adipose tissue ,Gene Expression ,medicine.disease_cause ,Antioxidants ,chemistry.chemical_compound ,Fumarates ,Rats, Inbred SHR ,Medicine and Health Sciences ,lcsh:Science ,Metabolic Syndrome ,Multidisciplinary ,Dimethyl fumarate ,C-Reactive Protein ,Physiological Parameters ,medicine.symptom ,Research Article ,medicine.medical_specialty ,Cardiology ,Inflammation ,Cardiovascular Pharmacology ,Spontaneously hypertensive rat ,Internal medicine ,medicine ,Genetics ,Lipolysis ,Animals ,Humans ,Pharmacology ,lcsh:R ,Hemodynamics ,Biology and Life Sciences ,medicine.disease ,Rats ,Oxidative Stress ,Endocrinology ,chemistry ,Dyslipidemia ,Pharmacogenetics ,Metabolic Disorders ,lcsh:Q ,Metabolic syndrome ,Transcriptome ,Oxidative stress ,Drug metabolism - Abstract
Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.
- Published
- 2014
14. Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats
- Author
-
Vladimír Landa, Olena Oliyarnyk, Hynek Strnad, Michal Pravenec, Ludmila Kazdova, Vaclav Zidek, Theodore W. Kurtz, Jan Silhavy, Miroslava Šimáková, and Petr Mlejnek
- Subjects
Biochemistry ,Fumaric Acid Esters ,business.industry ,Block (telecommunications) ,Transgene ,Medicine ,Pharmacology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested
- Published
- 2014
15. Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility
- Author
-
Ondrej Mihola, Vladimir Landa, Florencia Pratto, Kevin Brick, Tatyana Kobets, Fitore Kusari, Srdjan Gasic, Fatima Smagulova, Corinne Grey, Petr Flachs, Vaclav Gergelits, Karel Tresnak, Jan Silhavy, Petr Mlejnek, R. Daniel Camerini-Otero, Michal Pravenec, Galina V. Petukhova, and Zdenek Trachtulec
- Subjects
Rattus norvegicus ,Meiotic recombination ,PRDM9 ,Fertility ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Vertebrate meiotic recombination events are concentrated in regions (hotspots) that display open chromatin marks, such as trimethylation of lysines 4 and 36 of histone 3 (H3K4me3 and H3K36me3). Mouse and human PRDM9 proteins catalyze H3K4me3 and H3K36me3 and determine hotspot positions, whereas other vertebrates lacking PRDM9 recombine in regions with chromatin already opened for another function, such as gene promoters. While these other vertebrate species lacking PRDM9 remain fertile, inactivation of the mouse Prdm9 gene, which shifts the hotspots to the functional regions (including promoters), typically causes gross fertility reduction; and the reasons for these species differences are not clear. Results We introduced Prdm9 deletions into the Rattus norvegicus genome and generated the first rat genome-wide maps of recombination-initiating double-strand break hotspots. Rat strains carrying the same wild-type Prdm9 allele shared 88% hotspots but strains with different Prdm9 alleles only 3%. After Prdm9 deletion, rat hotspots relocated to functional regions, about 40% to positions corresponding to Prdm9-independent mouse hotspots, including promoters. Despite the hotspot relocation and decreased fertility, Prdm9-deficient rats of the SHR/OlaIpcv strain produced healthy offspring. The percentage of normal pachytene spermatocytes in SHR-Prdm9 mutants was almost double than in the PWD male mouse oligospermic sterile mutants. We previously found a correlation between the crossover rate and sperm presence in mouse Prdm9 mutants. The crossover rate of SHR is more similar to sperm-carrying mutant mice, but it did not fully explain the fertility of the SHR mutants. Besides mild meiotic arrests at rat tubular stages IV (mid-pachytene) and XIV (metaphase), we also detected postmeiotic apoptosis of round spermatids. We found delayed meiosis and age-dependent fertility in both sexes of the SHR mutants. Conclusions We hypothesize that the relative increased fertility of rat versus mouse Prdm9 mutants could be ascribed to extended duration of meiotic prophase I. While rat PRDM9 shapes meiotic recombination landscapes, it is unnecessary for recombination. We suggest that PRDM9 has additional roles in spermatogenesis and speciation—spermatid development and reproductive age—that may help to explain male-specific hybrid sterility.
- Published
- 2021
- Full Text
- View/download PDF
16. Generation and Phenotypic Analysis of a Transgenic Line of Rabbits Secreting Active Recombinant Human Erythropoietin in the Milk.
- Author
-
Tomás Mikus, Martin Poplstein, Jirina Sedláková, Vladimír Landa, and Gabriela Jeníková
- Abstract
Production of recombinant human erythropoietin (rhEPO) for therapeutic purposes relies on its expression in selected clones of transfected mammalian cells. Alternatively, this glycoprotein can be produced by targeted secretion into the body fluid of transgenic mammals. Here, we report on the generation of a transgenic rabbits producing rhEPO in the lactating mammary gland. Transgenic individuals are viable, fertile and transmit the rhEPO gene to the offspring. Northern blot data indicated that the expression of the transgene in the mammary gland is controlled by whey acidic protien (WAP) regulatory sequences during the period of lactation. While the hybridization with total RNA revealed the expression only in the lactating mammary gland, the highly sensitive combinatory approach using RT-PCR/hybridization technique detected a minor ectopic expression. The level of rhEPO secretion in the founder female, measured in the period of lactation, varied in the range of 60178 and 60162 mIU/ml in the milk and blood plasma, respectively. Biological activity of the milk rhEPO was confirmed by a standard [
3 H]-thymidine incorporation test. Thus, we describe the model of a rhEPO-transgenic rabbit, valuable for studies of rhEPO glycosylation and function, which can be useful for the development of transgenic approaches designed for the preparation of recombinant proteins by alternative biopharmaceutical production. [ABSTRACT FROM AUTHOR]- Published
- 2004
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.