The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension an d accompanying metabolic disturbances. Recent advances in sequencing of genomes of BN- Lx and SHR progenitors of the BXH/HXB recombinant inbred (RI) strains as well as ac cumulation of multiple data sets of intermediary phenotypes in the RI strains, including mRNA and microRNA abundance, quantitative metabolomics, proteomics, methylomics or histone modifications, will make it possible to systematically search for genetic variants involved in regulation of gene ex pression and in the etiology of complex pathophysiological traits. New advances in manipulation of the rat genome, including e fficient transgenesis and gene targeting, will enable in vivo functional analys es of selected candidate genes to identify QTL at the molecular level or to provide insight into mechanisms whereby targeted genes affect pathophysiological traits in the SHR., M. Pravenec ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Recently, we derived “humanized” spontaneously hypertensive rats (SHR-CRP) in which transgenic expression of human CRP induces inflammation, oxidative stress, several features of metabolic syndrome and target organ injury. In addition, we found that rosuvastatin treatment of SHR-CRP transgenic rats can protect against pro-inflammatory effects of human CRP and also reduce cardiac inflammation and oxidative damage. In the current study, we tested the effects of rosuvastatin (5 mg/kg) on kidney injury in SHR-CRP males versus untreated SHR-CRP and SHR controls. All rats were fed a high sucrose diet. In SHR-CRP transgenic rats, treatment with rosuvastatin for 10 weeks, compared to untreated transgenic rats and SHR controls, was associated with significantly reduced systemic inflammation which was accompanied with activation of antioxidative enzymes in the kidney, lower renal fat accumulation, and with amelioration of histopathological changes in the kidney. These findings provide evidence that, in the presence of high CRP levels, rosuvastatin exhibits significant anti-inflammatory, anti-oxidative, and renoprotective effects., J. Šilhavý, V. Zídek, V. Landa, M. Šimáková, P. Mlejnek, O. Oliyarnyk, H. Malínská, L. Kazdová, M. Mancini, M. Pravenec., and Obsahuje bibliografii
The growth capacity of cultured vascular smooth muscle cells (VSMC) obtained from the thoracic aorta of 8-week-old male and female spontaneously hypertensive rats (SHR) was compared. Explants from the intima- media complex were cultured in Dulbecco minimum essential medium supplemented with fetal calf serum (10 %). The migration of VSMC out of the explants started on day 2 in both sexes but on day 18 the number of explants with VSMC migration was 100 ±32 explants/flask in male VSMC and only 24 ±5 explants/flask in female ones. The doubling time at the early exponential phase of growth was shorter (13.5 ±0.5 h) and the p H]-thymidine Labelling Index was higher (34.0±2.3 %) in male VSMC than in those from females (19.9±0.6 h and 23.9±1.9 %, p<0.01, respectively). The difference in the doubling time became even more apparent in the late exponential phase of growth (male VSMC: 51.8±2.0 h, female VSMC: 91.5±5.8 h, p<0.001). Moreover, at the end of the exponential growth phase, the male VSMC reached significantly higher (pcO.OOl) maximum population density than VSMC from females. Our data provide evidence of different growth characteristics of cultured VSMC isolated from male and female SHR aortas.
It has been reported that the major function of the sterol regulatory element binding protein 2 (SREBP-2) is to activate preferentially cholesterol biosynthesis in liver and adipose tissue rather than fatty acid synthesis. In the current study, we analyzed the effects of overexpression of human dominantpositive SREBP-2 transgene under control of PEPCK promoter in the spontaneously hypertensive rat (SHR) on lipid and glucose metabolism. Transgenic overexpression of SREBP-2 was associated with significantly higher hepatic triglycerides (20.4±0.9 vs. 17.0±0.05 μmol/g, P<0.05) but not cholesterol (10.6±0.4 vs. 10.9±0.4 μmol/g) and decreased relative weight of epididymal fat pad (0.73±0.03 vs. 0.830.03, P<0.05). In addition, muscle triglyceride (15.8±3.7 vs. 8.5±1.2 μmol/g, P<0.001) and cholesterol (3.6±0.5 vs. 2.1±0.1 μmol/g, P<0.05) concentrations were significantly increased in transgenic rats when compared to SHR controls. Ectopic fat accumulation was associated with significantly increased serum glucose levels (6.4±0.1 vs. 5.9±0.1 mmol/l, P<0.005) and reduced insulin levels (1.78±0.33 vs. 2.73±0.37 nmol/l, P<0.05) in transgenic rats. These results provide evidence for important role of SREBP-2 in regulation of lipid and glucose metabolism., V. Landa, V. Zídek, P. Mlejnek, M. Šimáková, J. Šilhavý, J. Trnovská, L. Kazdová, M. Pravenec., and Obsahuje bibliografii
The growth response to angiotensin II (Ang II) was studied using cultured vascular smooth muscle cells (VSMC) isolated from the aortae of male and female spontaneously hypertensive rats (SHR). Systolic and mean arterial blood pressure of 10-week-old males was significantly higher when compared to age-matched females. The specific growth rate of male VSMC was significantly higher on the third and sixth day after synchronisation. Angiotensin II in concentration 10~7 M stimulated the specific growth rate only in male VSMC during the exponential phase of growth. Moreover, doubling time was 3 hours shorter in male VSMC in comparison with the females. Our results suggest that both the increased specific growth rate and augmented growth-response of male VSMC to Ang II may explain the higher sensitivity of males to hypertensive stimuli.