Biomedical subjects

Zdenka Pausova

Publications and source records attributed to Zdenka Pausova.

9 recordsLinked to original sources

PubMed2006

From big fat cells to high blood pressure: a pathway to obesity-associated hypertension.

PURPOSE OF REVIEW: The environment created by modern industrialized societies has caused an unprecedented rise in the prevalence of obesity and obesity-related disorders, including hypertension. Mechanisms that underlie the development of hypertension in obese individuals are not very well understood; they are thought to involve activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and oxidative stress. RECENT FINDINGS: Recent research suggests that obesity-associated hypertension may be causally related to the accumulation of 'dysfunctional' adipose tissue characterized by the presence of 'large' lipid-laden adipocytes. SUMMARY: Excess energy-intake leads to an expansion of adipose tissue, a hallmark of obesity. But morphology of the expanded adipose tissue differs across individuals, including the size of adipocytes. The presence of 'large' rather than 'small' adipocytes is associated with functional and structural abnormalities of adipose tissue. These include increased production of bioactive molecules, such as leptin, angiotensinogen, pro-inflammatory cytokines, and reactive oxygen species; insufficient capacity to accommodate excess energy-intake leading to ectopic fat storage in tissues and in turn insulin resistance and hyperinsulinemia; and augmented macrophage infiltration enhancing the production of pro-inflammatory cytokines and reactive oxygen species. Such a 'dysfunctional' adipose tissue may, in turn, induce activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and oxidative stress and, hence, promote the development of obesity-associated hypertension.

Adipocytes↗

PubMed2005

Genome-wide scan for linkage to obesity-associated hypertension in French Canadians.

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having > or =2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (> or =70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density <10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] score=2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD score=3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD score=3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder.

Atrial Natriuretic Factor↗

PubMed2005

Hyperaldosteronism and hypertension: ethnic differences.

The purpose of this study is to evaluate the relationship between aldosterone and blood pressure in a total of 220 normotensive and 293 essential hypertensive subjects in 2 genetically distinct populations-blacks and white French Canadians. The 24-hour blood pressure monitoring was performed under standardized conditions after discontinuing antihypertensive medications. Plasma renin activity and plasma aldosterone were measured in the supine position and after standing for 10 minutes. Plasma atrial natriuretic factor was also measured. Supine and standing plasma renin activities were lower (P< or =0.01), plasma aldosterone was higher (P<0.0001), and the aldosterone/renin ratios were higher (P<0.0001) in the hypertensive subjects. Atrial natriuretic factor was also higher in the hypertensive subjects (P<0.0001). Among blacks, blood pressures did not correlate with plasma renin activity. However, both average daytime and nighttime systolic and diastolic blood pressures were correlated with supine and standing plasma aldosterone and with the aldosterone/renin ratio (P<0.005 or less). In French Canadians, blood pressures tended to be positively correlated with standing plasma renin activity and aldosterone, but not with the aldosterone/renin ratio. Correlations of blood pressure with aldosterone were more consistent and more striking in blacks than in French Canadians. In both ethnic groups, there were inconsistent correlations of blood pressure with atrial natriuretic factor. These observations are consistent with the hypothesis that aldosterone-induced volume expansion is an important contributor to hypertension, especially in blacks.

Adult↗

PubMed2004

Rat model of familial combined hyperlipidemia as a result of comparative mapping.

Total genome scan was carried out in 266 F2 intercrosses from the Prague hypertriglyceridemic (HTG) rat that shares several clinical characteristics with human metabolic syndrome. Two loci for plasma triglycerides (TG) were localized on chromosome 2 (Chr 2) (LOD 4.4, 3.2). The first locus overlapped with the rat syntenic region of the human locus for the metabolic syndrome and for small, dense LDL, while the second overlapped with the syntenic region of another locus for small, dense LDL in humans by the comparative mapping approach. Loci for TG on rat Chr 13 (LOD 3.3) and Chr 1 (LOD 2.7) overlapped with the syntenic region of loci for human familial combined hyperlipidemia (FCHL) in Finnish and Dutch populations, respectively. The concordances of loci for TG localized in this study with previously reported loci for FCHL and its related phenotypes are underlying the generalized importance of these loci in dyslipidemia. These data suggest the close relationship between dyslipidemia in HTG rats and human FCHL, establishing a novel animal model for exploration of pathophysiology and therapy based on genomic determinants.

Animals↗

PubMed2003

Segment of rat chromosome 20 regulates diet-induced augmentations in adiposity, glucose intolerance, and blood pressure.

Previous linkage and association studies have suggested that a region of human chromosome 6 containing the tumor necrosis factor (TNF)-alpha gene is involved in the pathogenesis of obesity and obesity-associated hypertension. The aim of the present investigation was to establish whether a segment of rat chromosome 20 (RNO20), which also contains the TNF-alpha gene, determines diet-induced changes in adiposity and blood pressure (BP). The results showed that a transfer of the RNO20 segment from the normotensive Brown Norway (BN) rat onto the background of the spontaneously hypertensive rat (SHR) is associated with a significantly greater increase in adiposity, glucose intolerance, circulating leptin levels, and BP during 12-week, high-fat-diet feeding. In contrast, the transfer is not associated with significant changes in these variables during 12-week, normal-diet feeding. In addition, sequencing of the TNF-alpha gene revealed differences between SHR and BN in the 5'- and 3'-regulatory regions of the gene. Subsequent analyses of TNF-alpha gene expression in fat, muscle, and liver, however, did not provide support for the functional involvement of these differences. In summary, the investigated RNO20 segment contains 1 or more gene variants that affect adiposity, glucose tolerance, serum leptin levels, and BP, but only when the animals are exposed to a particular environment, ie, high-fat-diet feeding. Further studies are needed to identify genes mediating these effects. Considering current changes in our lifestyle involving an increased calorie and fat intake, we believe that gene-environment interactions, such as those described here, play an important role in the current epidemic of obesity and obesity-associated hypertension.

Adipose Tissue↗

PubMed2003

TA repeat variation, Npr1 expression, and blood pressure: impact of the Ace locus.

The activity of the atrial natriuretic peptide receptor (Npr1) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-Lx and of 40 TA in SHR was localized at position -943 relative to the transcription start site of the Npr1 gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of -1520 to -920 Npr1 promoter-SV40-luciferase fusion vector showed that the construct from BN-Lx stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-Lx construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-Lx and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and Npr1 mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the Ace gene. The highest basal guanylyl cyclase activity and Npr1 mRNA values were found in RIS with both genes (Npr1/Ace) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of Npr1 of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the Npr1 gene with consequences on diastolic blood pressure.

3T3 Cells↗

PubMed2002

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems.

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.

Animals↗

PubMed2002

Gender-specific correlates of leptin with hypertension-related phenotypes in African Americans.

Leptin may be a link in the relationship of obesity with hypertension. We evaluated associations of leptin with blood pressure (BP) in 54 normotensive and 114 hypertensive African American individuals. Plasma leptin was higher (P <.03) in hypertensive women than in normotensive women, although body mass index did not differ (30.5 +/- 0.5 v 30.2 +/- 0.8 kg/m(2)). After adjusting for obesity and insulin resistance, there were no significant relationships between leptin and BP; however, leptin independently predicted 28% of the variability of heart rate in hypertensive men (P <.01) and 18% of the variability of lithium clearance in hypertensive women (P <.01). Thus, in these obese hypertensive African American women, there is no direct or independent association of leptin with BP. However, leptin may contribute to hypertension in these women by increasing renal tubular sodium reabsorption.

Adult↗

PubMed2002

A genealogical study of essential hypertension with and without obesity in French Canadians.

OBJECTIVES: To investigate genetic homogeneity in a set of hypertensive families and in subsets chosen for high and low prevalence of obesity; and to compare fasting insulin and lipids, ion transport, and water homeostasis in the obese and lean families. RESEARCH METHODS AND PROCEDURES: The study was carried out in a relative population isolate of the Saguenay/Lac St. Jean region in Canada. Genetic homogeneity was evaluated with the mean coeffigcients of kinship (phi) and inbreeding (F) computed with ascending genealogies. Serum insulin and lipids were measured after overnight fasting. Total body water was estimated with bioelectrical impedance. Sodium-lithium countertransport and sodium-potassium co-transport were determined in freshly isolated erythrocytes. RESULTS: F and phi were increased in hypertensive families compared with families selected at random. F and phi were further increased within the subsets of obese and lean families. In addition, fasting insulin, total body water, sodium-lithium countertransport, and sodium-potassium co-transport were higher in the obese than in the lean families. The two subsets of families did not differ by fasting lipids. DISCUSSION: In the Saguenay/Lac St. Jean population, the degree of genetic homogeneity was increased in families selected for hypertension, and it was further increased in subsets of hypertensive families with high and low prevalence of obesity. This suggests that hypertension in lean and obese individuals may represent, at least in part, separate genetic entities. Some of the extra genes shared in common within the subsets may contribute to their differences in body weight, insulin sensitivity, ion transport, and water homeostasis.

Antiporters↗