Cold exposure of rats leads to ameliorated glucose and triglyceride utilization with fema les displaying better adaptation to a cold environment. In the current study, we used hairless rats as a model of increased thermo genesis and analyzed gender- related effects on parameters of lipid and glucose metabolism in the spontaneously hypertensive (SHR) rats. Specifically, we compared hairless coisogenic SHR- Dsg4 males and females harboring mutant Dsg4 (desmoglein 4) gene versus their SHR wild type controls. Two way ANOVA showed significant Dsg4 genotype (hairless or wild type) x gender interaction effects on palmitate oxidation in brown adipose tissue (BAT), glucose incorporation into BAT determined by microPET, and glucose oxidation in skeletal muscles. In addition, we observed significant interaction effects on sensitivity of muscle tissue to insulin action when Dsg4 genotype affected these metabolic traits in males, but had little or no effects in females. Both wild type and hairless females and hairless males showed increased glucose incorporation and palmitate oxid ation in BAT and higher tissue insulin sensitivity when compared to wild type males. These findings provide evidence for gender-related differences in metabolic adaptation required for increased thermogenesis. They are consistent with the hypothesis that increased glucose and palmitate utilization in BAT and muscle is associated with higher sensitivity of adipose and muscle tissues to insulin action, J. Trnovská, J. Šilhavý, V. Zídek, M. Šimáková, P. Mlejnek, V. Landa, S. Eigner, K. Eigner Henke, V. Škop, O. Oliyarnyk, L. Kazdová, T. Mráček, J. Houštěk, M. Pravenec., and Obsahuje bibliografii
A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F2 intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases., T. Ueno, J. Tremblay, J. Kuneš, J. Zicha, Z. Dobešová, Z. Pausová, A. Y. Deng, Y. Sun, H. J. Jacob, P. Hamet., and Obsahuje bibliografii
Total genome scans of genetically segregating populations derived from spontaneously hypertensive rats (SHR) and other rat models of essential hypertension suggested a presence of quantitative trait loci (QTL) regulating blood pressure on multiple chromosomes, including chromosome 5. The objective of the current study was to test directly a hypothesis that chromosome 5 of the SHR carries a blood pressure regulatory QTL. A new congenic strain was derived by replacing a segment of chromosome 5 in the SHR/Ola between the D5Wox20 and D5Rat63 markers with the corresponding chromosome segment from the normotensive Brown Norway (BN/Crl) rat. Arterial pressures were directly monitored in conscious, unrestrained rats by radiotelemetry. The transfer of a segment of chromosome 5 from the BN strain onto the SHR genetic background was associated with a significant decrease of systolic blood pressure, that was accompanied by amelioration of renal hypertrophy. The heart rates were not significantly different in the SHR compared to SHR chromosome 5 congenic strain. The findings of the current study demonstrate that gene(s) with major effects on blood pressure and renal mass exist in the differential segment of chromosome 5 trapped within the new SHR.BN congenic strain., M. Pravenec, V. Křen, D. Křenová, V. Zídek, M. Šimáková, A. Musilová, J. Vorlíček, E. St. Lezin, T. W. Kurtz., and Obsahuje bibliografii
Graves' disease affects approximately 3 % of women and 0.5 % of men. The first-choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1 , DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid-specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants., D. Vejrazkova, J. Vcelak, E. Vaclavikova, M. Vankova, K. Zajickova, M. Duskova, J. Vrbikova, B. Bendlova., and Obsahuje bibliografii
The issue of plasma triglyceride levels relative to the risk of development of cardiovascular disease, as well as overall mortality, has been actively discussed for many years. Like other cardiovascular disease risk factors, final plasma TG values have environmental influences (primarily dietary habits, physical activity, and smoking), and a genetic predisposition. Rare mutations (mainly in the lipoprotein lipase and apolipoprotein C2) along with common polymorph isms (within apolipoprotein A5, glucokinase regulatory protein, apolipoprotein B, apolipo - protein E, cAMP responsive element binding protein 3 -like 3 , glycosylphosphatidylinositol- anchored HDL -binding protein 1) play an important role in determining plasma TG levels., L. Schwarzova, J. A. Hubacek, M. Vrablik., and Obsahuje bibliografii
Genetic strain-dependent reactivity to mechanical stimuli in rat skeletal muscle has not been examined. This study aimed to examine whether genetic strain-dependency is associated with reactivity in protein metabolism and the resultant muscle hypertrophy after isometric resistance training (RT). The right triceps of Sprague-Dawley (SD) and Wistar rats underwent 12 sessions of RT. After RT, a transition from the IIb to the IIx myosin heavy-chain isoform was observed in both strains. In SD rats, the lateral gastrocnemius muscle (LG) mass of the trained legs (TRN) was significantly higher than that of the control legs (CON) (7.8 %, P<0.05). Meanwhile, in Wistar rats, the LG mass was unchanged. In SD rats, the levels of 70-kDa ribosomal protein S6 kinase (p70S6k) and forkhead box 3a (FOXO3a) phosphorylation in the TRN were significantly greater than those of the CON (2.2- and 1.9-fold, respectively; P<0.05). The expression of muscle ring finger-1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin-1) in the TRN were significantly lower than those of the CON (0.6- and 0.7-fold, respectively; P<0.05). However, in Wistar rats, there was no significant difference. These results suggest a genetic strain difference in protein metabolism. This phenomenon may be useful for studying individual differences in response to RT., K. Kobayashi ... [et al.]., and Obsahuje seznam literatury
Type 1 diabetes mellitus (DM 1A) is an autoimmune disease belonging to the most frequent chronic diseases of the childhood and young adults. DM 1A results from immune-mediated destruction of the insulin-producing beta cells of the pancreas. It is a genetically determined disease and many genes or genetic regions were found to be associated with its induction. In addition to the insulin-dependent diabetes mellitus 1 (IDDM1) gene, which marks the HLA region, and IDDM2 which marks the insulin gene, significant associations of DM 1A to other IDMM genes or genetic regions we reported. We shortly review recent achievements in the field, and the state of current knowledge., D. Kantárová, M. Buc., and Obsahuje bibliografii a bibliografické odkazy
A common variant of the LHb subunit has a varying prevalence in various ethnic groups. The consequences of the presence of mutated luteinizing hormone (LH) concern borderline alterations in pituitary/gonadal function that could be mediated by an altered action of variant LH on gonadal steroidogenesis. A comparison of plasma concentrations of gonadal steroid sex hormones was completed in women heterozygous for variant LH and in women with the wild type of LH in three different age ranges. The sample was a randomly selected group of 177 normal women 16 to 72 years old. Variant LH was determined by immunofluorimetric methods using two combinations of monoclonal antibodies. The ratios of LH measured by the two assays indicated whether the subject was wild type homozygote, heterozygote or homozygote for the variant LHb allele. The carriers of the variant LH allele in the group of postmenopausal women showed higher serum testosterone levels than those with the wild type LH. This is in agreement with the clinical observations made previously showing a slightly higher androgenic action in the population with variant LH. No differences were detected in serum LH, FSH, epitestosterone and sex hormone binding globulin (SHBG)., M. Hill, I.T. Huhtaniemi, R. Hampl, L. Stárka., and Obsahuje bibliografii
Mutations in troponin T (TNNT2) gene represent the important part of currently identified disease-causing mutations in hypertrophic (HCM) and dilated (DCM) cardiomyopathy. The aim of this study was to analyze TNNT2 gene exons in patients with HCM and DCM diagnosis to improve diagnostic and genetic consultancy in affected families. All 15 exons and their flanking regions of the TNNT2 gene were analyzed by DNA sequence analysis in 174 patients with HCM and DCM diagnosis. We identified genetic variations in TNNT2 exon regions in 56 patients and genetic variations in TNNT2 intron regions in 164 patients. Two patients were found to carry unique mutations in the TNNT2 gene. Limited genetic screening analysis is not suitable for routine testing of disease-causing mutations in patients with HCM and DCM as only individual mutation-positive cases may be identified. Therefore, this approach cannot be recommended for daily clinical practice even though, due to financial constraints, it currently represents the only available strategy in a majority of cardio-centers., M. Jáchymová ... [et al.]., and Obsahuje seznam literatury
Increased levels of plasma cysteine are associated with obesity and metabolic disturbances. Our recent genetic analyses in spontaneously hypertensive rats (SHR) revealed a mutated Folr1 (folate receptor 1) as the quantitative trait gene associated with diminished renal Folr1 expression, lower plasma folate levels, hypercysteinemia, hyperhomocysteinemia and metabolic disturbances. To further analyse the effects of the Folr1 gene expression on folate metabolism, we used mass spectrometry to quantify folate profiles in the plasma and liver of an SHR-1 congenic strain, with wild type Folr1 allele on the SHR genetic background, and compared them with the SHR strain. In the plasma, concentration of 5-methyltetrahydrofolate (5mTHF) was significantly higher in SHR-1 congenic rats compared to SHR (60±6 vs. 42±2 nmol/l, P<0.01) and 5mTHF monoglutamate was the predominant form in both strains (>99 % of total folate). In the liver, SHR-1 congenic rats showed a significantly increased level of 5mTHF and decreased concentrations of dihydrofolate (DHF), tetrahydrofolate (THF) and formyl-THF when compared to the SHR strain. We also analysed the extent of folate glutamylation in the liver. Compared with the SHR strain, congenic wild-type Folr1 rats had significantly higher levels of 5mTHF monoglutamate. On the other hand, 5mTHF penta- and hexaglutamates were significantly higher in SHR when compared to SHR-1 rats. This inverse relationship of rat hepatic folate polyglutamate chain length and folate sufficiency was also true for other folate species. These results strongly indicate that the whole body homeostasis of folates is substantially impaired in SHR rats compared to the SHR-1 congenic strain and might be contributing to the associated metabolic disturbances observed in our previous studies., M. Pravenec, K.-Y. Leung, V. Zídek, P. Mlejnek, M. Šimáková, J. Šilhavý, V. Kožich, N. D. E. Greene., and Obsahuje bibliografii