Beta-adrenergic receptors (beta-ARs) play a pivotal role in the cardiovascular regulation. In the human heart beta1- and beta2-ARs dominate in atria as well as in ventricle influencing heart rate and myocardial contractility. Some single nucleotide polymorphisms (SNPs) of beta-ARs might influence cardiovascular function. However, the influence of beta-AR genes SNPs on hemodynamic parameters at rest and their reactivity under stress is still not well known. We aimed to explore the associations between four selected beta-ARs gene polymorphisms and selected cardiovascular measures in eighty-seven young healthy subjects. While in beta1-AR polymorphism rs1801252 no significant association was observed, second beta1-AR polymorphism rs1801253 was associated with decreased cardiac output and cardiac index during all phases and with decreased flow time corrected and ejection time index at rest and during mental arithmetics. Polymorphism rs1042713 in beta2-AR was associated with alterations in blood pressure variability at rest and during head-up-tilt, while rs1042714 was associated predominantly with decreased parameters of cardiac contractility at rest and during mental arithmetics. We conclude that complex analysis of various cardiovascular characteristics related to the strength of cardiac contraction and blood pressure variability can reveal subtle differences in cardiovascular sympathetic nervous control associated with beta-ARs polymorphisms.

• MeSH
• beta-1-adrenergní receptory genetika   MeSH
• beta-2-adrenergní receptory genetika   MeSH
• fenotyp MeSH
• funkce levé komory srdeční genetika   MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• kontrakce myokardu genetika   MeSH
• krevní tlak genetika   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIMS/HYPOTHESIS: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. METHODS: We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 individuals with type 2 diabetes in the UK Biobank study. RESULTS: The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events (p = 6.3 × 10-21 and p = 9.6 × 10-31, respectively) and a 4.4-fold (p = 6.8 × 10-33) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk individuals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. CONCLUSIONS/INTERPRETATION: This novel multiPRS model stratified individuals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.

• MeSH
• celogenomová asociační studie MeSH
• diabetes mellitus 2. typu * komplikace   genetika   MeSH
• komplikace diabetu * komplikace   MeSH
• krevní glukóza MeSH
• krevní tlak genetika   MeSH
• lidé MeSH
• multifaktoriální dědičnost * MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

It is widely accepted that sympathetic nervous system plays a crucial role in the development of hypertension. On the other hand, the role of adrenal medulla (the adrenomedullary component of the sympathoadrenal system) in the development and maintenance of high blood pressure in man as well as in experimental models of hypertension is still controversial. Spontaneously hypertensive rats (SHR) are the most widely used animal model of human essential hypertension characterized by sympathetic hyperactivity. However, the persistence of moderately elevated blood pressure in SHR subjected to sympathectomy neonatally as well as the resistance of adult SHR to the treatment by sympatholytic drugs suggests that other factors (including enhanced activity of the adrenomedullary hormonal system) are involved in the pathogenesis of hypertension of SHR. This review describes abnormalities in adrenomedullary hormonal system of SHR rats starting with the hyperactivity of brain centers regulating sympathetic outflow, through the exaggerated activation of sympathoadrenal preganglionic neurons, to the local changes in chromaffin cells of adrenal medulla. All the above alterations might contribute to the enhanced release of epinephrine and/or norepinephrine from adrenal medulla. Special attention is paid to the alterations in the expression of genes involved in catecholamine biosynthesis, storage, release, reuptake, degradation and adrenergic receptors in chromaffin cells of SHR. The contribution of the adrenomedullary hormonal system to the development and maintenance of hypertension as well as its importance during stressful conditions is also discussed.

• MeSH
• dřeň nadledvin metabolismus   patofyziologie   MeSH
• hormony metabolismus   MeSH
• hypertenze genetika   metabolismus   patofyziologie   MeSH
• krevní tlak genetika   MeSH
• lidé MeSH
• potkani inbrední SHR MeSH
• sympatický nervový systém patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Suboptimal conditions during prenatal and early postnatal development can increase risk of hypertension later in life. We studied consequences of a changed perinatal environment by initiating the cross-fostering of homozygous Ren-2 transgenic rat (TGR) offspring to normotensive, transgene-negative control mothers, and vice versa. We hypothesized that cross-fostering to a normotensive female can attenuate the development of malignant hypertension in TGR offspring (TGRx) and change their salt-sensitive response. Blood pressure (BP) was monitored by the telemetry system under normal salt intake, and BP responses to increased salt intake in the phase of established hypertension. Under normal salt conditions, BP was not markedly different in cross-fostered animals compared with controls. However, BP responses to 2% salt intake led to a stronger BP response in TGRx during the active phase when compared with the control TGR group. The TGRx also exhibited increased albuminuria, lower sodium excretion, and creatinine clearance under higher salt intake compared with control salt intake. Higher salt intake resulted in a significant increase of aldosterone concentrations only in the TGRx group; moreover, TGRx rats exhibited more pronounced renal injury compared with controls. In conclusion, our data indicate that cross-fostering in TGR not only did not attenuate the development of hypertension but, on the contrary, led to the deterioration of BP regulation, particularly due to exaggerated salt sensitivity and sodium retention in TGRx. Results underline the important role of the mother during lactation in postnatal development of the offspring, since these changes reflected different ion content in milk of a particular strain of rats.

• MeSH
• aldosteron krev   MeSH
• hypertenze genetika   patofyziologie   MeSH
• krevní tlak genetika   fyziologie   MeSH
• krysa rodu rattus MeSH
• ledviny patofyziologie   MeSH
• potkani transgenní MeSH
• renin-angiotensin systém fyziologie   MeSH
• renin genetika   MeSH
• sodík dietní * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase μ-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke-prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. METHOD: Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF-1α promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1 and SHRSP-Tg(Gstm1)2]. RESULTS: Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2 ± 3.7 mmHg vs. SHRSP-Tg(Gstm1)1 175.5 ± 1.6 mmHg and SHRSP-Tg(Gstm1)2 172 ± 3.2 mmHg, P < 0.001; pulse pressure: SHRSP 58.4 ± 0.73 mmHg vs. SHRSP-Tg(Gstm1)1 52.7 ± 0.19 mmHg and SHRSP-Tg(Gstm1)2 40.7 ± 0.53 mmHg, P < 0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification (RQ): SHRSP-Tg(Gstm1)1 1.95 vs. SHRSP 1.0, P < 0.01; aorta RQ: SHRSP-Tg(Gstm1)1 2.8 vs. SHRSP 1.0, P < 0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidized : reduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04 ± 0.009 μmol/l vs. SHRSP-Tg(Gstm1)1 0.024 ± 0.002 μmol/l and SHRSP-Tg(Gstm1)2 0.021 ± 0.002 μmol/l; (oxidized : reduced glutathione ratio): SHRSP 5.19 ± 2.26 μmol/l vs. SHRSP-Tg(Gstm1)1 0.17 ± 0.11 μmol/l and SHRSP-Tg(Gstm1)2 0.47 ± 0.22 μmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. CONCLUSION: These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.

• MeSH
• aorta metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• glutathion metabolismus   MeSH
• glutathiontransferasa genetika   metabolismus   MeSH
• hypertenze genetika   patofyziologie   MeSH
• krevní tlak genetika   MeSH
• krysa rodu rattus MeSH
• ledviny metabolismus   MeSH
• malondialdehyd metabolismus   MeSH
• oxidační stres genetika   MeSH
• peroxidace lipidů MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• potkani transgenní MeSH
• systola MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Metabolic syndrome and one of its manifestations, essential hypertension, is an important cause of worldwide morbidity and mortality. Morbidity and mortality associated with hypertension are caused by organ complications. Previously we revealed a decrease of blood pressure and an amelioration of cardiac fibrosis in a congenic line of spontaneously hypertensive rats (SHR), in which a short segment of chromosome 8 (encompassing only 7 genes) was exchanged for a segment of normotensive polydactylous (PD) origin. To unravel the genetic background of this phenotype we compared heart transcriptomes between SHR rat males and this chromosome 8 minimal congenic line (PD5). We found 18 differentially expressed genes, which were further analyzed using annotations from Database for Annotation, Visualization and Integrated Discovery (DAVID). Four of the differentially expressed genes (Per1, Nr4a1, Nr4a3, Kcna5) belong to circadian rhythm pathways, aldosterone synthesis and secretion, PI3K-Akt signaling pathway and potassium homeostasis. We were also able to confirm Nr4a1 2.8x-fold upregulation in PD5 on protein level using Western blotting, thus suggesting a possible role of Nr4a1 in pathogenesis of the metabolic syndrome.

• MeSH
• fenotyp MeSH
• fibróza MeSH
• funkce levé komory srdeční genetika   MeSH
• genetická predispozice k nemoci MeSH
• hypertenze genetika   metabolismus   patofyziologie   MeSH
• kardiomyopatie genetika   metabolismus   patologie   MeSH
• krevní tlak genetika   MeSH
• metabolický syndrom genetika   metabolismus   patofyziologie   MeSH
• modely nemocí na zvířatech MeSH
• potkani inbrední SHR MeSH
• regulace genové exprese MeSH
• remodelace komor genetika   MeSH
• signální transdukce genetika   MeSH
• srdeční komory metabolismus   patologie   MeSH
• stanovení celkové genové exprese * MeSH
• transkriptom * MeSH
• zvířata kongenní MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

OBJECTIVE: The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine metabolism; meanwhile reactive oxygen species are formed. We hypothesized that uric acid production, as assessed indirectly from XOR variants, is associated with hypertension. METHODS: Among 2769 participants (48.3% men; mean age 40.7 years) randomly recruited from European populations, we genotyped 25 tagging XOR SNPs and measured blood pressure (BP) at baseline and follow-up (median 8.8 years). The relation between variants of the XOR gene with changes in pulse pressure and mean arterial pressure over time; and incidence of hypertension, were analyzed. RESULTS: Compared with nonminor allele carriers, pulse pressure increased approximately 2 mmHg more in minor allele carriers of rs11904439 (P = 0.01), whereas mean arterial pressure and DBP increased approximately 1 mmHg less in minor allele carriers of rs2043013 (P = 0.01). In 2050, participants normotensive at baseline, hazard ratios contrasting risk of hypertension in minor allele carriers vs. nonminor allele carriers were 1.31 (95% confidence interval 1.03-1.68; P = 0.02) and 1.69 (95% confidence interval 1.11-2.57; P = 0.01) for rs11904439 and rs148756340, respectively. With the false discovery rate set at 0.25, the aforementioned associations retained significance. The changes in SBP from baseline to follow-up and the serum levels of uric acid at baseline (n = 1949) were not associated with XOR. CONCLUSION: Pending confirmation, our findings suggest that variation in uric acid production, as captured by genetic variation in XOR, might be a predictor of changes in BP and in the risk of hypertension.

• MeSH
• arteriální tlak genetika   MeSH
• běloši genetika   MeSH
• diastola genetika   MeSH
• dospělí MeSH
• genotyp MeSH
• heterozygot MeSH
• hypertenze epidemiologie   genetika   MeSH
• incidence MeSH
• jednonukleotidový polymorfismus MeSH
• krevní tlak genetika   MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• následné studie MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• xanthinoxidasa genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Belgie epidemiologie   MeSH
• Česká republika epidemiologie   MeSH
• Itálie epidemiologie   MeSH
• Polsko epidemiologie   MeSH
• Rusko epidemiologie   MeSH

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.

• MeSH
• adrenalin metabolismus   MeSH
• dopamin-beta-hydroxylasa biosyntéza   genetika   MeSH
• dopamin metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• hypertenze genetika   patofyziologie   MeSH
• komplementární DNA biosyntéza   genetika   MeSH
• krevní tlak genetika   MeSH
• krysa rodu rattus MeSH
• mozkový kmen metabolismus   MeSH
• nadledviny enzymologie   MeSH
• noradrenalin metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• regulace genové exprese enzymů genetika   MeSH
• transgeny MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine.

• MeSH
• biologické modely MeSH
• hmotnostní přírůstek genetika   MeSH
• hypertenze genetika   patofyziologie   MeSH
• krevní tlak genetika   MeSH
• lidé MeSH
• metabolický syndrom genetika   patofyziologie   MeSH
• multifaktoriální dědičnost genetika   MeSH
• obezita genetika   patofyziologie   MeSH
• sympatický nervový systém patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• Dieta DASH (Dietary Approaches to Stop Hypertension),
• MeSH
• ateroskleróza etiologie   prevence a kontrola   MeSH
• dítě MeSH
• draslík metabolismus   škodlivé účinky   terapeutické užití   MeSH
• hypertenze etiologie   prevence a kontrola   MeSH
• kardiovaskulární nemoci * etiologie   prevence a kontrola   MeSH
• krevní tlak genetika   imunologie   účinky léků   MeSH
• kuchyňská sůl * metabolismus   škodlivé účinky   MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• mladiství MeSH
• rizikové faktory MeSH
• senioři MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• sodík metabolismus   škodlivé účinky   MeSH
• statistika jako téma MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• senioři MeSH
• Publikační typ
• multicentrická studie MeSH
• přehledy MeSH