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Anna F Dominiczak

Publications and source records attributed to Anna F Dominiczak.

At least 19 recordsLinked to original sources
PubMed2007

Studies of an association in boys of blood pressure and the Y chromosome.

BACKGROUND: Variations in the Y chromosome have shown significant, albeit inconsistent, associations with hypertension in men. Studies of peripubertal subjects might reveal more information on the origins of the Y chromosome's influence on blood pressure (BP). In the current study, we examined the association of a HindIII restriction site on the Y chromosome with BP in a cohort of young men. METHODS: Pubertal growth-based analyses were performed in 80 unrelated males with multiple measurements spanning time points beginning before and extending to after their pubertal growth. Blood pressure, height, and weight were measured approximately every 6 months. The period of pubertal growth was used to approximate the time for puberty. The association of the HindIII restriction site to systolic and diastolic BP was determined using a mixed model ANOVA. RESULTS: Estimated systolic and diastolic BPs were higher in HindIII(-) males in the period before, as well as in the period after pubertal growth (systolic BP 2.6 +/- 1.3 mm Hg higher, P < .05), and diastolic BP 2.3 +/- 1.2 mm Hg higher, P = .050). In addition, HindIII(-) males were younger at onset of peak height velocity (12.7 +/- 0.1 v 13.3 +/- 0.1 years, P < .001). In African Americans, an earlier age of maximal height velocity was associated with a higher systolic and diastolic BP (P < .05 and .02, respectively). CONCLUSIONS: The results suggest that variations in genes on the Y chromosome may affect BP in peripubertal males, possibly even before onset of puberty.

Adolescent↗
PubMed2006

Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.

The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.

Adrenal Cortex Hormones↗
PubMed2006

Generation Scotland: the Scottish Family Health Study; a new resource for researching genes and heritability.

BACKGROUND: Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. METHODS/DESIGN: Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. DISCUSSION: As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.

Adolescent↗
PubMed2006

Increased support for linkage of a novel locus on chromosome 5q13 for essential hypertension in the British Genetics of Hypertension Study.

Human hypertension arises from a combination of genetic factors and lifestyle influences. With cardiovascular disease set to become the number 1 cause of death worldwide, it is important to understand the etiologic mechanisms for hypertension, because these might provide new routes to improved treatment. The British Genetics of Hypertension Study has recently published a primary genome screen that identified 4 chromosomal regions of interest. We have now genotyped additional markers to confirm the most promising regions for follow-up studies. Thirty-four additional microsatellites were genotyped in our severely hypertensive affected sibling pair resource (now 1635 families with 2142 affected sibling pairs), leading to a substantial increase in information content in the regions of interest. We found increased support for linkage of chromosome 5q13 to human hypertension (multipoint logarithm of odds=2.50) with 3 adjacent markers yielding single point logarithm of odds scores of 3.22, 2.84, and 2.51. The placement of additional markers on 2q, 6q, and 9q diminished support for linkage in these regions. However, the addition of new data and families identified novel regions of interest on chromosomes 1q and 11q. The 3 positive markers in the chromosome 5 region were also genotyped in 712 distinct parent-offspring trios with the same severe phenotype to replicate linkage and association. Borderline support for replication was found (P=0.07). We found increased evidence for linkage and borderline-significant evidence for association for a hypertension susceptibility locus on chromosome 5q13 that is worthy of detailed fine mapping and assessment of candidate genes.

Chromosome Mapping↗
PubMed2006

Chromosome 2p shows significant linkage to antihypertensive response in the British Genetics of Hypertension Study.

There is a lack of consistently linked loci influencing blood pressure and hypertension status, and this may be because of genetic or phenotypic heterogeneity. We hypothesize that stratification of subjects by response to antihypertensive drug groups could be used to stringently define subsets that will have reduced genetic and etiologic heterogeneity, by partitioning contrasting mechanisms of hypertension and, thus, enhancing gene finding. We investigated the British Genetics of Hypertension Study population, which is composed of 2142 severely hypertensive white affected sibling pairs. Nonresponse to antihypertensive therapy was defined as an on-treatment blood pressure of >140/90 mm Hg or a difference between prediagnosis and on-treatment blood pressure of <20 mm Hg. Of the nonresponders, there were 89 sibling pairs (AB) who were both on antihypertensive therapy that inhibit the renin-angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, or beta-blockers), and 76 sibling pairs (CD) who were both on drugs that do not (calcium channel blockers or diuretics). Nonparametric linkage analysis carried out using markers from a 10-cM genome scan and additional "grid tightening" markers showed significant linkage in the AB group on chromosome 2p (logarithm of odds=4.84 at 90.68 Kosambi cM) and suggestive linkage for the CD group on chromosome 10q (logarithm of odds=2.83 at 125.96 Kosambi cM). The AB linkage locus attained genomewide significance after simulation using 10,000 replicates (P=0.005). This locus may contain a gene for the salt-sensitive form of hypertension and/or a pharmacogenetic locus affecting drug response. We have demonstrated for the first time identification of a significant locus by partitioning different pathways of hypertension using drug response.

Adrenergic beta-Antagonists↗
PubMed2006

Genetic information in the diagnosis and treatment of hypertension.

Advancement in cardiovascular science should be measured by a number of new diagnostic and therapeutic options applied in clinical practice as a result of translational research. Hypertension genetics is a good example of such a successful transfer of knowledge from bench to bedside. There are genetic methods currently used as diagnostic tools in patients presenting with secondary forms of hypertension, including primary hyperaldosteronism, Cushing's syndrome, pheochromocytoma, and chronic kidney disease. Directed treatment that corrects pathophysiologic abnormalities is available for several monogenic forms of hypertension as a result of uncovering their underlying genetic mechanisms. Progress in hypertension pharmacogenetics and pharmacogenomics brings closer a perspective of personalized antihypertensive treatment and gene transfer strategies, which, although still considered as innovative approaches, may soon become options to treat, control, and, possibly, cure hypertension.

Adrenocortical Hyperfunction↗
PubMed2006

Estrogen treatment enhances nitric oxide bioavailability in normotensive but not hypertensive rats.

BACKGROUND: The effects of estrogen on endothelial function remain controversial. Endothelial function is perturbed in hypertension. We aimed to determine whether pre-existing hypertension can modify endothelial-dependent responses to estrogen. METHODS: We compared the effects of estrogen replacement on endothelial function in healthy female adult Wistar Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). Basal and carbachol-stimulated nitric oxide (NO) bioavailability were studied in carotid artery rings in ovariectomized animals treated with estrogen or placebo for 2 weeks in vivo, or after 1 h of incubation in vitro. Basal NO bioavailability was defined as the increase in pressor responses in phenylephrine in the presence of NO synthase blockade. Superoxide (O(2)(-)) levels in aortas were measured by lucigenin chemiluminescence and endothelial NO synthase (eNOS) protein levels by Western blotting. RESULTS: Basal NO bioavailability was increased in WKY treated with estrogen for 2 weeks compared to placebo. In contrast, no change in NO bioavailability was observed in SHRSP. The O(2)(-) levels were higher in SHRSP than in WKY but unaffected by estrogen treatment in either strain. In WKY, but not in SHRSP, estrogen caused upregulation of eNOS. Similarly in vitro exposure to estrogen increased NO bioavailability in WKY but had no effect in SHRSP. In WKY, co-exposure to estrogen and LY294002, a PI3 kinase inhibitor, abrogated the effect of estrogen. CONCLUSIONS: The inability of estrogen to improve endothelial function in SHRSP may relate to a defect in eNOS activation pathways in this hypertensive rat strain.

Animals↗
PubMed2006

Functional genomics in hypertension.

PURPOSE OF REVIEW: Essential hypertension is a complex polygenetic disease with a major impact on health worldwide. Despite earlier detection of promising candidate genes, only recent advances in genotyping technology and new approaches to examining gene and protein function have provided the tools to unravel the genetic basis of hypertension. RECENT FINDINGS: In humans, genome-wide scans resulted in the identification of several chromosomal loci that are linked to hypertension. These regions still contain a large number of potential candidate genes, but high-throughput genotyping methods will facilitate the detection and analysis of single-nucleotide polymorphisms within these genes. The focus will be on animal models of hypertension, specifically rats. Congenic strains facilitate the identification of genetic determinants of hypertension, and new technologies such as RNA interference (which silences the expression of target genes) and transgenic rescue models will help us to analyse the relationship between genes and function. Analysis of conserved synteny (preserved order of genes) between species allows translation of findings from rodent models to essential hypertension in humans. Recent discoveries and approaches beyond genomics will also be discussed, including the regulatory role of microRNA and the concept of proteomics. SUMMARY: The genetic basis of hypertension is complex, and the examination of the functional consequences of genetic variants in particular is still challenging. A number of tools are now available with which to examine gene-function relationships, and these will provide an improved understanding of cardiovascular genomics. This will eventually lead to targeted prevention and treatment strategies in patients with hypertension and other cardiovascular diseases.

Animals↗
PubMed2005

Low-density lipoprotein cholesterol determines oxidative stress and endothelial dysfunction in saphenous veins from patients with coronary artery disease.

OBJECTIVE: There is evidence for a relationship between endothelial dysfunction and cardiovascular disease, but a causative role for oxidative stress remains to be determined. METHODS AND RESULTS: We studied 188 patients with severe coronary artery disease (CAD), of whom 51 were age and sex matched with 51 healthy controls undergoing varicose vein surgery. Relaxation of saphenous vein to calcium ionophore, apocynin, and allopurinol was studied together with the markers of oxidative stress, total antioxidant capacity and reduced/oxidized glutathione ratio. Vascular superoxide levels were measured using lucigenin chemiluminescence and hydroethidine. Relaxation to calcium ionophore was decreased in CAD compared with control patients (maximum relaxation 26+/-2% versus 60+/-1%; P<0.001). Total superoxide production was increased (0.89+/-0.09 versus 0.56+/-0.06 nmol/mg per min; P=0.008), whereas superoxide inhibition with apocynin or allopurinol had a greater effect on vasorelaxation in CAD patients. Low-density lipoprotein (LDL) cholesterol predicted relaxation to calcium ionophore (P<0.001) and oxidative stress markers (P<0.001) in CAD patients. CONCLUSIONS: Endothelial dysfunction is associated with raised levels of superoxide and biomarkers of oxidative stress in saphenous veins from CAD patients. LDL cholesterol is a major determinant of endothelial dysfunction and oxidative stress in these patients. These results support intensive LDL cholesterol-lowering therapy as suggested by recent clinical trials.

Acetophenones↗
PubMed2005

Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats.

Cerebral blood flow (CBF) is maintained constant despite changes in systemic blood pressure (BP) through multiple mechanisms of autoregulation such as vascular myogenic reactivity. Our aim was to determine myogenic characteristics of cannulated middle cerebral arteries (MCA) in male and female stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) at 12 wk of age under pressurised no-flow conditions. MCA pressure-diameter relationships (20-200 mmHg) were constructed in active (with calcium) and passive (without calcium) conditions, and myogenic and mechanical properties were determined. Myogenic reactivity in WKY (P < 0.05) and SHRSP (P < 0.05) males was impaired compared with their female counterparts. Comparison of SHRSP with WKY in males revealed similar myogenic reactivity, but in females SHRSP exhibited augmented myogenic reactivity (P < 0.05). In both sexes, myogenic tone yielded at lower pressure in SHRSP compared with WKY vessels (120-140 vs. 140-180 mmHg). Stress-strain relationships and elastic moduli in WKY rats showed that vessels were stiffer in females than in males. Conversely, in SHRSP, male vessels were stiffer than female vessels. Comparison of strains in males indicated that stiffness was increased in SHRSP compared with WKY vessels, whereas the converse was observed in females. These findings demonstrate that MCA myogenic and distensibility characteristics exhibit significant sex- and strain-dependent differences. Inappropriate myogenic adaptation and augmented vascular stiffness, particularly in male SHRSP, are potential limiting factors in blood flow autoregulation and may increase the predisposition for stroke-related cerebrovascular events.

Animals↗
PubMed2005

Corcoran Lecture. Cardiovascular genomics and oxidative stress.

The majority of modifiable cardiovascular risk factors are complex, polygenic, or at least oligogenic traits, with genetic and environmental determinants playing important roles in disease risk and its phenotypic expression. The Human Genome Project and subsequent mouse and rat genome data have provided powerful tools to commence the dissection of genetic determinants of hypertension and other cardiovascular risk factors. Despite several new methodologies such as genome-wide scans, genome-wide gene expression profiling, and proteomic screens, it is fair to say that the progress of genetic studies designed as nonhypothesis driven has been relatively slow. On the other hand, several interesting candidate pathways have been identified, where investigators allowed for hypothesis-driven functional studies. One example of such pathway is vascular oxidative stress with its extensive network of genes and proteins, many with proven contributions to cardiovascular disease. Therefore, in parallel to genome-wide or proteome-wide studies, it will be constructive to pursue "pathwayomics" defined here as functional studies of a candidate pathway for disease pathogenesis.

Animals↗
PubMed2005

Reduction of Gstm1 expression in the stroke-prone spontaneously hypertension rat contributes to increased oxidative stress.

Human essential hypertension is a classic example of a complex, multifactorial, polygenic disease with a substantial genetic influence in which the underlying genetic components remain unknown. The stroke-prone spontaneously hypertension rat (SHRSP) is a well-characterized experimental model for essential hypertension and endothelial dysfunction. Previous work, identified glutathione S-transferase mu type 1, a protein involved in detoxification of reactive oxygen species, as a positional and functional candidate gene. Quantitative real-time polymerase chain reaction showed a highly significant, 4-fold reduction of glutathione S-transferase mu type 1 mRNA expression in 5- and 16-week-old SHRSP compared with the congenic and normotensive Wistar Kyoto rats. This suggests that differential expression is not attributable to long-term changes in blood pressure. DNA sequencing identified one coding single nucleotide polymorphism (R202H) and multiple single nucleotide polymorphisms in the promoter region. mRNA expression changes were reflected at the protein level, with significant reductions in the SHRSP glutathione S-transferase mu type 1. Protein was colocalized with aquaporin 2 to the principle cells of the renal collecting ducts. Coupled to significant increases in nitrotyrosine levels in the kidney, this suggests a pathophysiological role of this protein in hypertension and oxidative stress. Similar processes may underlie oxidative stress in the vasculature.

Amino Acid Sequence↗
PubMed2005

Targeting endothelial cells with adenovirus expressing nitric oxide synthase prevents elevation of blood pressure in stroke-prone spontaneously hypertensive rats.

Local adenoviral (Ad)-mediated gene transfer to the carotid artery of the stroke-prone spontaneously hypertensive rat (SHRSP) is successful in improving endothelial function. Here we explored the potential of systemic delivery of Ad encoding endothelial nitric oxide synthase (AdeNOS) to prevent elevation of blood pressure in the SHRSP using both nontargeted and vector targeting approaches. Systemic administration of nontargeted AdeNOS failed to modify the rise in blood pressure in SHRSP when administered during the 12th week of age (n = 5, P = 0.088, F = 3.0), an effect likely to result from sequestration of Ad by the liver. Rerouting Ad transduction using a bispecific antibody (anti-ACE/anti-Ad capsid, Fab9B9) that blocks Ad binding to the coxsackie and adenovirus receptor and simultaneously retargets AdeNOS to the angiotensin-converting enzyme resulted in efficient eNOS overexpression in the lung vasculature and a sustained hypotensive effect (n = 5, P = 0.007, F = 7.9). This study highlights the importance of vector targeting to achieve therapeutic gain and represents the first such study in cardiovascular gene therapy.

Adenoviridae↗
PubMed2005

Vascular responses to IGF-I and insulin are impaired in aortae of hypertensive rats.

OBJECTIVE: Insulin-like growth factor-I (IGF-I) and insulin are important vasoactive peptides but little is known about their effects in hypertension. DESIGN: We compared the responses of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rat aortae to IGF-I and insulin. METHODS: Aortae were removed from WKY and SHRSP, cut into 2-3 mm rings, and contractile responses to phenylephrine and endothelin-1 studied in organ chambers in the presence of vehicle, IGF-I (0.1 micromol/l) or insulin (0.1 micromol/l). In addition, the effects of nitric oxide synthase (NOS) inhibition, phosphatidylinositol 3-kinase (PI3-kinase) inhibition and superoxide scavenging on these responses were investigated. RESULTS: Incubation with IGF-I and insulin caused attenuation of phenylephrine-induced and endothelin-1-induced vasoconstriction in arteries from normotensive but not hypertensive animals. In the arteries from WKY rats, co-incubation with either wortmannin or LY294002, inhibitors of PI3-kinase, attenuated the effect of IGF-I. The vasorelaxant effect of IGF-I was also abolished by removal of the endothelium or addition of the NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Co-incubation with tiron, a superoxide scavenger, suggested that the attenuation of IGF-I vasodilation in SHRSP arteries was not due to excess superoxide production. CONCLUSION: In WKY, IGF-I/insulin attenuate phenylephrine-mediated constrictions via PI3-kinase/nitric oxide pathways. In contrast, in SHRSP these pathways are dysfunctional and IGF-I has little effect on vascular responses.

Androstadienes↗
PubMed2005

Genetic determinants of metabolic syndrome components in the stroke-prone spontaneously hypertensive rat.

OBJECTIVE: The metabolic syndrome is a complex multifactorial disease, which results from interactions between genes on multiple chromosomes and environmental factors. Animal models may facilitate genetic analysis of complex phenotypes by allowing complete control of environmental conditions and the ability to produce designer strains. METHODS: Stroke-prone spontaneously hypertensive (SHRSP) and Wistar-Kyoto (WKY) rat strains were used to construct congenic (SP.WKYGla2a), consomic (SP.WKYGlaYw, WKY.SPGlaYs) and double-introgressed (SP.WKYGla2aYw) strains, which were characterized for metabolic syndrome phenotypes (systolic blood pressure, glucose tolerance and lipid profile) after feeding a 60% fructose diet for 14 days. RESULTS: The Y consomic strain (SP.WKYGlaYw) demonstrated that the WKY Y chromosome significantly lowered triglyceride levels (3.77 +/- 0.60 versus 9.09 +/- 1.47 mmol/l; P < 0.001) and improved glucose tolerance [area under the curve (AUC): 26.93 +/- 0.81 versus 31.47 +/- 0.89; P < 0.05] compared with SHRSP. The chromosome 2 congenic strain (SP.WKYGla2a) exhibited significantly improved glucose tolerance (AUC: 28.19 +/- 1.17 versus 31.47 +/- 0.89; P < 0.05) and lower systolic blood pressure (161.2 +/- 6.2 versus 179.7 +/- 3.9 mmHg; P < 0.05) compared with SHRSP. 2 x 2 factorial ANOVA identified a significant interaction for glucose metabolism (P = 0.004) in the double-introgressed strain (SP.WKYGla2aYw) between chromosome 2 and Y. CONCLUSIONS: These results identify novel interacting regions on chromosome 2 and the Y chromosome influencing a cluster of metabolic and cardiovascular phenotypes. Translation to clinical studies will facilitate genetic dissection of human metabolic syndrome.

Animals↗