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Haralambos Gavras

Publications and source records attributed to Haralambos Gavras.

At least 37 records · Page 2Linked to original sources
PubMed2004

Cardiac transcriptional response to acute and chronic angiotensin II treatments.

Exposure of experimental animals to increased angiotensin II (ANG II) induces hypertension associated with cardiac hypertrophy, inflammation, and myocardial necrosis and fibrosis. Some of the most effective antihypertensive treatments are those that antagonize ANG II. We investigated cardiac gene expression in response to acute (24 h) and chronic (14 day) infusion of ANG II in mice; 24-h treatment induces hypertension, and 14-day treatment induces hypertension and extensive cardiac hypertrophy and necrosis. For genes differentially expressed in response to ANG II treatment, we tested for significant regulation of pathways, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Microarray Pathway Profiler (GenMAPP) databases, as well as functional classes based on Gene Ontology (GO) terms. Both acute and chronic ANG II treatments resulted in decreased expression of mitochondrial metabolic genes, notably those for the electron transport chain and Krebs-TCA cycle; chronic ANG II treatment also resulted in decreased expression of genes involved in fatty acid metabolism. In contrast, genes involved in protein translation and ribosomal activity increased expression following both acute and chronic ANG II treatments. Some classes of genes showed differential response between acute and chronic ANG II treatments. Acute treatment increased expression of genes involved in oxidative stress and amino acid metabolism, whereas chronic treatments increased cytoskeletal and extracellular matrix genes, second messenger cascades responsive to ANG II, and amyloidosis genes. Although a functional linkage between Alzheimer disease, hypertension, and high cholesterol has been previously documented in studies of brain tissue, this is the first demonstration of induction of Alzheimer disease pathways by hypertension in heart tissue. This study provides the most comprehensive available survey of gene expression changes in response to acute and chronic ANG II treatment, verifying results from disparate studies, and suggests mechanisms that provide novel insight into the etiology of hypertensive heart disease and possible therapeutic interventions that may help to mitigate its effects.

Angiotensin II↗
PubMed2004

Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice.

Hypertension is a complex phenotype induced by multiple environmental and genetic factors. Quantitative trait locus (QTL) analysis is a powerful method for identifying genomic regions underlying complex diseases. We conducted a QTL analysis of blood pressure in mice using 217 F(2) progeny (males and females) from a cross between the normotensive C3H/HeJ and hypertensive SWR/J inbred strains. Our analysis identified significant QTL controlling blood pressure on chromosome 1 [Chr 1; Bpq8; peak 78 cM; 95% confidence interval 64-106 cM; logarithm of the odds ratio (LOD) 3.5; peak marker D1Mit105] and on Chr 16 (Bpq9; peak 56 cM; 95% confidence interval 46-58 cM; LOD 3.6; peak marker D16Mit158). Bpq8 was previously identified in a cross between C57BL/6J and A/J mice, and we narrowed this QTL from 42 to 18 cM (95% confidence interval 68-86 cM) by combining the data from these crosses. By examining Bpq8 for regions where ancestral alleles were conserved among the high allele strains (C57BL/6J, SWR/J) and different from the low allele strains (A/J, C3H/HeJ), we identified a 2.3-cM region where the high allele strains shared a common haplotype. Bpq8 is concordant with known QTL in both rat and human, suggesting that the causal gene underlying Bpq8 may be conserved as a disease gene in human hypertension.

Animals↗
PubMed2004

Mitochondrial genome mutations in hypertensive individuals.

Human essential hypertension (HTN), a polygenic, multifactorial, and highly heterogeneous disorder of unknown etiology, has been shown to have excess maternal transmission in several studies, suggesting a possible mitochondrial involvement. In an effort to assess the contribution of the mitochondrial genome to HTN we initiated a systematic, extended screening of hypertensive individuals to identify potentially pathogenic mtDNA mutations. We applied our newly developed novel class of tests for the detection of mitochondrial mutation involvement in complex diseases to the hypertension data set from 350 pedigrees of white ethnicity and 98 of African American ethnicity ascertained at HTN clinics associated with Boston Medical Center, and we identified families with a likely mitochondrial involvement. We analyzed the sequence of the entire mitochondrial genome in probands from 20 such pedigrees, consisting of 10 African American and 10 white families. Comparison with the reference "Cambridge" sequence revealed a total of 297 base changes, including 24 in the ribosomal RNA (rRNA) genes, 15 in the transfer RNA (tRNA) genes, and 46 amino acid substitutions, with the remainder involving the noncoding regions or synonymous changes. Among the coding region mutations, 30 are novel, with 13 hypertensive probands carrying at least one novel variant, usually in combination with the previously described common polymorphisms, several of which are associated with cardiovascular and renal pathologies. These data will serve as a starting point for large-scale case-control association studies.

Black People↗
PubMed2004

Endothelin-aldosterone interaction and proteinuria in low-renin hypertension.

OBJECTIVE: To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension. DESIGN: Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15). METHODS: Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion. RESULTS: Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467). CONCLUSIONS: Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.

Adult↗
PubMed2003

Serial analysis of gene expression in mouse kidney following angiotensin II administration.

As a new line of inquiry into the molecular mechanisms underlying pathophysiological processes associated with angiotensin (ANG II)-dependent hypertension, we applied the method of serial analysis of gene expression (SAGE) to examine genome-wide transcription changes in the kidneys of mice that developed hypertension in response to chronic ANG II administration. Mice were infused subcutaneously via osmotic minipumps with ANG II for 7 days, and systolic blood pressure was measured by tail-cuff plethysmography. Subsequently, mice were euthanized, and the total RNA isolated from the kidneys was used to construct SAGE libraries. Comparison of 11,447 SAGE tags from the hypertensive kidneys, representing 5,740 unique transcripts, and 11,273 tags from the control kidneys, corresponding to 5,619 different transcripts, identified genes that are significantly (P < 0.05) down- or upregulated in the hypertensive kidney. Our assessment of the genome-wide influence of ANG II resulted in the detection of several novel genes and in a recognition of potential new roles for the previously characterized genes, thus providing new probes with which to further explore the ANG II effects in normal and disease states.

Angiotensin II↗
PubMed2003

Mechanisms mediating the vasoactive effects of the B1 receptors of bradykinin.

Bradykinin normally exerts its vasodilatory effect via the B2 receptor (B2R), but in this receptor's absence, the B1 receptor becomes expressed and activated. To explore the mechanism of B1R-mediated vasodilation, 8 groups of B2R gene-knockout mice received a 2-week infusion of a B1R antagonist (300 microg x kg(-1) x d(-1)) or vehicle (groups 1 and 2), B1R antagonist or vehicle plus NO inhibition with Nomega-nitro-L-arginine methyl ester (groups 3 and 4), B1R antagonist or vehicle plus cyclooxygenase inhibition with indomethacin (groups 5 and 6), or B1R antagonist or vehicle plus blockade of vasoconstricting prostaglandin (PG) H2 and thromboxane A2 (TxA2) with SQ29548 (groups 7 and 8). The B1R antagonist produced significant (P<0.05) blood pressure increases of 17.7+/-3.1 mm Hg in group 1 and 10.4+/-3 mm Hg in group 3, whereas their vehicle-treated respective control groups 2 and 4 had no significant blood pressure changes. Indomethacin abolished the capacity of the B1R antagonist to raise blood pressure, as did blockade of the receptors of PGH2 and TxA2. Injection with the B1R agonist produced a hypotensive response (12+/-1.3 mm Hg), which was further accentuated by TxA2 blockade (21.7+/-4.1 mm Hg). Analysis of B1R gene expression by reverse transcription-polymerase chain reaction (PCR) in cardiac and renal tissues revealed marked expression at baseline, with further upregulation by 1.5- to 2-fold after various manipulations. Expression of the TxA2 receptor gene in renal tissue by quantitative real-time PCR was significantly lower in mice treated with the B1R antagonist, consistent with increased levels of agonist for this receptor. The data confirm that the B1R becomes markedly expressed in the absence of B2R and suggest that it contributes to vasodilation by inhibiting a vasoconstricting product of the arachidonic acid cascade acting via the PGH2/TxA2 receptor.

Animals↗
PubMed2003

A novel class of tests for the detection of mitochondrial DNA-mutation involvement in diseases.

We develop a novel class of tests to detect mitochondrial DNA (mtDNA)-mutation involvement in complex diseases by the study of affected pedigree members. For a pedigree, affected individuals are first considered and are then connected through their relatives. We construct a reduced pedigree from an original pedigree. Each configuration of a reduced pedigree is given a score, with high scores given to configurations that are consistent with mtDNA-mutation involvement and low scores given to configurations that are not consistent with mtDNA-mutation involvement. For many pedigrees, the weighted sum of scores of the pedigrees is calculated. The tests are formed by comparing the observed score with the expected score under the null hypothesis that only nuclear autosomal mutations are involved. We study the optimality of score functions and weights under the heterogeneity model without phenocopies. We also develop a method to estimate the contribution that mtDNA mutations make if they are involved under a heterogeneity model. Finally, we apply our methods to three data sets: Leber hereditary optic neuropathy, a disease that has been proved to be caused by mtDNA mutations; non-insulin-dependent diabetes mellitus (NIDDM); and hypertension (HTN). We find evidence of mtDNA-mutation involvement in all three diseases. The estimated fraction of patients with NIDDM due to mtDNA-mutation involvement is 22% (95% confidence interval [CI] 6%-38%). The fraction of patients with HTN potentially due to mtDNA-mutation involvement is estimated at 55% (95% CI 45%-65%).

DNA Mutational Analysis↗
PubMed2003

Genetic variants of WNK4 in whites and African Americans with hypertension.

Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P=0.027) or without (P=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Africa↗
PubMed2003

The effect of rapid decreases of blood pressure by different mechanisms on coronary flow and flow reserve in normal coronary arteries.

BACKGROUND: Changes in mean blood pressure (MBP) alter coronary blood flow (CBF). We evaluated the acute effects of three hypotensive medications on CBF parameters in angiographically normal coronary arteries. METHODS: We performed CBF measurements using the Doppler wire at rest and during hyperemia produced by intracoronary adenosine (18 microg) as follows: 1) in the normal left circumflex coronary artery in 20 patients with coronary artery disease (measurements were performed without drugs, and after intravenous infusion of nitroprusside [0.5 to 2 microg/kg/min] and nitroglycerin [10 to 90 microg/min]; drugs were titrated to decrease MBP 20% to 25% below the control values, and heart rate was held constant using right atrial pacing); and 2) in the normal left anterior descending coronary artery in 19 patients without coronary artery disease (measurements were performed before and after intravenous clonidine infusion [150 microg in 5 min]; time-averaged peak velocity [APV], CBF, and coronary flow reserve [CFR] were measured). RESULTS: Similar decreases in MBP were obtained in the two patient groups. Lumen diameter at the site of Doppler measurements increased after all medications (P <.005), whereas CBF did not change significantly. The CFR decreased after nitroprusside (1.79 +/- 0.48 v 2.54 +/- 0.45, P=.000), did not change significantly after nitroglycerin (2.74 +/- 0.43 v 2.54 +/- 0.45, P =.097), and increased after clonidine (3.12 +/- 0.70 v 2.76 +/- 0.75, P =.006). CONCLUSIONS: In normal coronary arteries the infusion of three hypotensive medications to produce the same decreases in MBP is associated with different effects on CFR (increase with clonidine, decrease with nitroprusside, and no change with nitroglycerin).

Aged↗
PubMed2003

Association of polymorphisms in the promoter region of the PNMT gene with essential hypertension in African Americans but not in whites.

BACKGROUND: Several studies have indicated that a region on human chromosome 17 may influence blood pressure. Our group reported positive linkage for hypertension to the region on human chromosome 17, between D17S1814 and D17S800 in white sibling pairs. In this study, we further investigated this result by examining the phenylethanolamine N-methyltransferase (PNMT) gene, which is located at 17q21 within the region where we found linkage. METHODS: A case/control association study was conducted to evaluate the relationship between genetic variants of the PNMT gene and risk for essential hypertension. Two single nucleotide polymorphisms (SNPs) in the promoter region of the gene were genotyped, PNMT-148 and PNMT-353, in three ethnic samples: African American (117 hypertensive, 96 normotensive), American white (91 hypertensive, 80 normotensive), and Greek white (99 hypertensive, 90 normotensive), using the homogeneous mass extend reaction (Sequenom) and RFLP for genotyping. RESULTS: A significant difference in allelic frequency of SNP-353 between hypertensives (38.02%) and normotensives (27.35%) in African Americans (P =.019) was found; however, no significant differences were observed for this SNP for the other ethnic groups. No association was found with SNP PNMT-148 in any of the ethnic groups. Frequencies of haplotypes based on the two SNPs were also compared between hypertensive and normotensive individuals. No significant difference was found in estimated haplotype frequencies between hypertensive and control subjects in the three ethnic groups. CONCLUSIONS: These results suggest that genetic variants of PNMT may play a role in the development of essential hypertension.

Black or African American↗
PubMed2003

Central alpha2B-adrenergic receptor antisense in plasmid vector prolongs reversal of salt-dependent hypertension.

OBJECTIVE: Previous studies have shown that a fully functional alpha(2B)-adrenergic receptor (AR) is necessary for the development of salt-induced hypertension. The current studies were designed to explore the effect of prolonged inhibition of central alpha(2B)-AR gene expression by antisense (AS) DNA on this hypertension. METHODS: We developed a plasmid vector driven by a cytomegalovirus promoter, containing a green fluorescent protein reporter gene and AS for rat alpha(2B)-AR protein. Subtotally nephrectomized, salt-loaded hypertensive rats received intracerebroventricular injection of 500 microg of either the AS plasmid (n = 9) or sense plasmid (containing cDNA for alpha(2B)-AR), as control (n = 7). RESULTS: The AS injection produced a fall in SBP from 201 +/- 4 to 171 +/- 5 mmHg within 12 h. The level of BP in the 3 days post-injection was 174 +/- 6, 181 +/- 4 and 184 +/- 6 mmHg on day 1, day 2 and day 3, respectively (P < 0.05), and returned gradually towards baseline in subsequent days, although it remained significantly lower for the 8 days of observation. The control sense plasmid injections produced no significant changes in blood pressure (BP). Neither group had histological evidence of neural tissue disruption. CONCLUSIONS: These results indicate that protracted translational inhibition of the alpha(2B)-AR gene in the central nervous system can be obtained by AS DNA delivered via plasmid vector and lead to decreased generation of alpha(2B)-AR protein, which can partly reverse salt-induced hypertension for several days.

Animals↗
PubMed2002

Role of vasopressin in 24-hour blood pressure regulation in diabetic patients with autonomic neuropathy.

To evaluate the role of vasopressin (AVP) on blood pressure (BP) in diabetic patients with autonomic neuropathy (AN), 10 patients were studied on a fixed sodium and potassium diet. On days 4 and 7, a 24-h BP monitoring, as well as blood and urine samples for sodium, potassium, creatinine, and osmolality determinations were obtained for every 4-h period; either placebo or an AVP-V1-antagonist (d(CH2)5Tyr(me)AVP; 0.5 mg; AVPi) were given iv at 1 PM. On placebo, systolic BP (SBP) showed a progressive elevation during the day, declining after 12 PM (8 AM to 12 AM 122+/-9; 12 AM to 4 PM 125+/-11; 4 PM to 8 PM 134+/-14; 8 PM to 12 PM 136+/-14; 12 PM to 8 AM 131+/-17 mm Hg). On AVPi this rise in SBP was blunted: 8 AM to 12 AM 125+/-122; 12 AM to 4 PM 121+/-21; 4 PM to 8 PM 126+/-16; 8 PM to 12 PM 129+/-14; 12 PM to 8 AM 124+/-12 mm Hg. Creatinine clearance and diureses were greater during the night, both with placebo and AVPi. Plasma osmolality did not change on either day, although serum sodium decreased after AVPi, reaching the lowest values at 4 PM to 8 PM period (137+/-4.7 v 131+/-3.8 mEq/L; P < .05). With placebo, fractional excretion of sodium (FENa) increased from 0.43%+/-0.32% during 12 h of orthostasis to 0.92%+/-1.05% during 12 h of recumbency (P < .02). With AVPi, the FENa on orthostasis did not differ from that with placebo, although BP values were lower and did not increase with recumbency (0.58+/-0.57 v 0.73%+/-0.49%; NS). In conclusion, our results show that in diabetic patients with AN, vasopressin participates in BP control by stimulating vascular and renal V1 receptors, which results in vasoconstriction and sodium reabsorption.

Adult↗