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
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
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
Metabolic disorders such as obesity, insulin resistance and other components of metabolic syndrome (MetS) are connected with birth weight. Low and high birth weight is associated with a higher risk of developing type 2 diabetes mellitus, the mechanism is not clear. In this study, we evaluated the association between birth weight and anthropometric as well as biochemical components of MetS in women with a history of gestational diabetes mellitus (GDM) in comparison with control women. In part of the GDM group, we re-evaluated metabolic changes over 5-8 years. Anthropometry, blood pressure, glucose metabolism during the 3-h oGTT, lipid profile, uric acid, thyroid hormones, and liver enzymes were assessed. From the analyzed components of MetS in adult women we proved the association of low birth weight (birth weight <25th percentile) with glucose processing, in particular among women with a history of GDM. Low birth weight GDM women revealed significantly higher postchallenge insulin secretion and lower peripheral insulin sensitivity. Re-examinations indicate this association persists long after delivery., D. Vejrazkova, P. Lukasova, M. Vankova, O. Bradnova, G. Vacinova, J. Vcelak, V. Cirmanova, K. Andelova, H. Krejci, B. Bendlova., and Obsahuje bibliografii
Ghrelin is a new endogenous peptide, discovered in 1999 by Kojima et al., as the result of a search for an endogenous ligand for an orphan receptor of known structure and function. Ghrelin is composed of 28 amino acids and is produced mostly by cells of the stomach, hypothalamus, and hypophysis, but it has also been detected in other tissues. Its discovery is related to the development of a new hypothesis regarding the regulation of growth hormone secretion. It is an antagonist of somatostatin. Ghrelin activates the release of growth hormone from the somatotrophic cells of the hypophysis. It participates in the regulation of energy homeostasis, increases food intake, decreases energy output and exerts a lipogenetic effect. Its metabolic effects do not depend on the GH/IGF-I system, but are mediated by the NPY/Y1 and AGRP receptor system. Ghrelin influences the secretion and motility of the gastrointestinal tract, especially the stomach. The presence of ghrelin and its receptors has also been demonstrated in many other tissues. Its function in these tissues has not yet been studied, thus providing many possibilities for further research., M. Rosická, M. Kršek, Z. Jarkovská, J. Marek, V. Schreiber., and Obsahuje bibliografii
In order to elucidate the direct effect of glucose on lipolysis in isolated rat adipocytes, cells were incubated in a buffer with different concentrations of this sugar: 2, 8 or 16 mmol/l. The increase in glucose concentration from 2 mmol/l to 8 or 16 mmol/l enhanced basal lipolysis by 30% and 47 %, respectively. Epinephrine-induced lipolysis (1 m mol/l) was also increased by 31 % and 32 %, when glucose concentration was increased from 2 mmol/l to 8 or 16 mmol/l, respectively. The rise in lipolysis caused by glucose was restricted by H-89 (an inhibitor of protein kinase A, 30 µmol/l), but insulin (1 nmol/l) had no inhibitory action. The augmentation of lipolysis by glucose did not require its metabolism (as demonstrated using 2-deoxyglucose) and was due to the action of this sugar on the final steps of the lipolytic cascade, particularly on protein kinase A. However, short-term exposure of adipocytes to higher glucose concentrations did not restrict the inhibitory action of insulin on lipolysis induced by epinephrine., T. Szkudelski, K. Szkudelska., and Obsahuje bibliografii