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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Variants of the human angiotensinogen gene have been linked in some studies to increased circulating angiotensinogen levels and essential hypertension. To test for direct causality between genotypes at the angiotensinogen locus and blood pressures, we have studied mice carrying zero, one, two, three, or four functional copies of the murine wild-type angiotensinogen gene (Agt) at its normal chromosomal location. Plasma angiotensinogen levels increase progressively, although not linearly, from zero in the zero-copy animals to 145% of normal in the four-copy animals. Mice of all genotypes are normal at birth, but most zero-copy animals die before weaning. The kidneys of the zero-copy animals show pathological changes as adults, but the kidneys are normal in the other genotypes. One adult zero-copy male tested was fertile. The blood pressures of the one-copy through four-copy animals show significant and almost linear increases of approximately 8 mmHg per gene copy despite their normal compensatory mechanisms being intact. These results establish a direct causal relationship between Agt genotypes and blood pressures.
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PMID:Genetic control of blood pressure and the angiotensinogen locus. 770 16

Several intervention studies with angiotensin I converting enzyme (ACE) inhibitors have demonstrated a remarkable improvement in the treatment of patients with primary hypertension and congestive heart failure. Since ACE inhibitor therapy in patients with congestive heart failure not only improves systemic haemodynamics but also provides a better prognosis, the cardiac renin-angiotensin system is apparently one of the major targets of ACE inhibitor therapy. Recent studies provided evidence that the human heart contains high affinity Ang II (Ang II) receptors with both subtype population and ACE. In addition to ACE, a novel cardiac Ang II forming enzyme (human chymase) has been identified in human hearts. Unlike in the rat heart, the minor (10%) component of Ang II-forming activity in the left ventricle is due to ACE, whereas the major (80%) component is due to human chymase. This novel cardiac serine proteinase has been purified from the human left ventricle and characterized, and recently, the cDNA and the gene for this enzyme have been cloned. Biochemical characterization revealed that human chymase is the most efficient and specific Ang II-forming enzyme described thus far, but the cellular and regional distribution of the two Ang II-forming enzymes seems to be different. ACE is mainly localized in endothelial cells and fibroblasts and the expression level is higher in atria than ventricles, whereas chymase is synthesized and stored in secretory granules of mast cells, endothelial cells, and mesenchymal cells, and after its secretion localized in the interstitial region of the myocardium and its expression is higher in ventricles than atria. These results imply distinct roles of these two Ang II-forming enzymes in cardiac Ang II formation and in the physiological function of the human heart. Since localization of cardiac renin and angiotensinogen were also identified in human heart, it is important to understand the detailed mechanisms of the tissue Ang II formation and its contribution to the pathophysiological changes in cardiovascular diseases.
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PMID:Tissue angiotensin II system in the human heart. 771 17

A molecular variant of the angiotensinogen gene with threonine instead of methionine at position 235 (ie, with M235T polymorphism) has been shown to be associated with essential hypertension in Caucasian populations. The purpose of the present study was to assess whether the M235T polymorphism was associated with essential hypertension in the Japanese population. The study population consisted of 347 subjects selected in our outpatient clinic. The clinical data included in the analyses were sex, age, body mass index, cholesterol level, genotype of the angiotensinogen gene, genotype of the angiotensin-converting enzyme gene, and systolic and diastolic blood pressure. Multiple regression analysis revealed that only body mass index was a predictor of both diastolic and systolic blood pressure in these 347 subjects, but the genotype of the angiotensinogen gene was identified as a predictor of both diastolic and systolic blood pressure in a subpopulation less than 50 years of age. However, in a subpopulation more than 50 years of age, body mass index was the only predictor of both systolic and diastolic blood pressure. Of the 347 subjects, 189 had a technically excellent echocardiogram at the initial observation period. Multiple regression analysis revealed that sex, body mass index, diastolic blood pressure, and genotype of the angiotensin-converting enzyme gene were predictors of left ventricular mass. Although subjects with the TT angiotensinogen genotype had significantly greater left ventricular mass than those with either the TM or the MM genotype, the effects of the genotype of the angiotensinogen gene on left ventricular mass were mainly due to effects on blood pressure.
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PMID:Angiotensinogen gene and blood pressure in the Japanese population. 772 17

Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues. In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in Km (from 1.1 to 0.09 microM) and a 5-fold decrease in kcat (from 1.0 to 0.22 s-1); as a result, catalytic efficiency (kcat/Km) is increased by a factor of 2 (1.1 versus 2.4 microM-1 s-1). In the reaction of angiotensin-converting enzyme on angiotensin decapeptides, the substitution has no effect on Km (38.0 versus 30.0 microM), but increases kcat and catalytic efficiency > 2-fold (kcat = 15.0 versus 37.0 s-1; kcat/Km = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.
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PMID:A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. 774 80

Allelic variants at the human angiotensinogen locus have recently been reported to increase susceptibility to the development of essential hypertension. In this study we analyzed the role played by angiotensinogen in the elevated blood pressure of the spontaneously hypertensive rat (SHR). The SHR angiotensinogen locus (on chromosome 19) cosegregated with a significant (P = .003) and specific increase in pulse pressure in F2 rats derived from a cross of the SHR with the normotensive Wistar-Kyoto rat (WKY), accounting for 20% of the genetic (10% of total) variance in this phenotype. To identify potential mechanisms underlying the effect of the locus, we further examined angiotensinogen structure and expression in the two strains. Sequence analysis of the respective coding regions revealed no differences in the primary structure of angiotensinogen between the strains. Likewise, plasma angiotensinogen level did not differ in adult rats of the two strains. However, gene expression studies showed tissue-specific, age-related differences in angiotensinogen mRNA levels between SHR and WKY, particularly in the aorta. The findings suggest that pulse pressure, which significantly influences cardiovascular risk, has independent genetic determinants. They further suggest that the effect of the angiotensinogen locus on this phenotype in the SHR may be mediated through a tissue-specific abnormality of angiotensinogen gene expression.
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PMID:Analysis of the role of angiotensinogen in spontaneous hypertension. 776 69

The renin-angiotensin system is a major determinant of arterial pressure and volume homeostasis in mammals through the actions of angiotensin II, the proteolytic digestion product of angiotensinogen. Molecular genetic studies in several human populations have revealed genetic linkage between the angiotensinogen gene and both hypertension and increased plasma angiotensinogen. Transgenic mice were generated with a human angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if overexpression of angiotensinogen results in hypertension. Human angiotensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proximal convoluted tubules. Plasma levels of human angiotensinogen were approximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiotensinogen gene was normal but infusion of a single bolus dose of purified human renin resulted in a transient increase in blood pressure of approximately 30 mm Hg within 2 min. These results suggest that abnormalities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.
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PMID:Functional expression of the human angiotensinogen gene in transgenic mice. 779 51

Recent advances in the genetics of hypertension include studies on localizations of many loci involved in blood pressure regulation in the rat, elucidation of the molecular mechanisms underlying monogenetic forms of hypertension, and studies of candidate genes in primary hypertension. Evidence that the angiotensinogen gene is involved in primary hypertension has been found by linkage in affected sibling pairs, and by the demonstration of increased risk of disease associated with DNA variants of the gene. Similar evidence of linkage and association has been found in preeclampsia, which suggests that the two diseases share at least one common factor of genetic susceptibility.
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PMID:Genetic basis of hypertension. 784 70

Recently, evidence has been presented for genetic linkage between the angiotensinogen gene and primary hypertension in humans. In the present study we examined whether a similar linkage between blood pressure and the angiotensinogen gene locus can be demonstrated in a widely used animal model of primary hypertension, the stroke-prone spontaneously hypertensive rat (Heidelberg colony, SHRSPHD). In 115 F2 hybrids bred from SHRSPHD and a normotensive reference strain, the Wistar-KyotoHD (WKYHD) rat, systolic and diastolic blood pressures and heart rate were determined by indwelling arterial catheters in the presence and absence of dietary sodium loading. In addition, left and right ventricular heart weight was measured. Using a newly developed polymorphic marker assay for the angiotensinogen gene based on polymerase chain reaction amplification of an exon 2 fragment and subsequent restriction endonuclease digestion, we performed a cosegregation study in this cohort. No evidence for cosegregation between the angiotensinogen gene locus and blood pressure or any other phenotypic parameter assessed was found. Although the SHRSP serves as a valuable model of hypertension, our data emphasize that disease-relevant genetic loci in humans and rats cannot be assumed to coincide.
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PMID:Unlike human hypertension, blood pressure in a hereditary hypertensive rat strain shows no linkage to the angiotensinogen locus. 791 49

Unravelling of the molecular mechanisms of the action of RAS has been slow. Nature has been rather stingy in revealing bits and pieces of information. Each step of development has depended on the innovation of an appropriate methodology. The uniqueness of the RAS lies in: The function and regulation of the highly specific enzyme renin which specifically catalyses the conversion of the prohormone angiotensinogen to Ang I by an extracellular mechanism. The production of the agonist Ang II takes place in two steps. Ang II and its metabolites exert exceedingly diverse pathophysiological effects, presumably through the complex and multifunctional receptors. The exquisite mechanisms involved in the regulation of renin release and receptor regulation are fascinating. The intricate mechanisms that nature has devised for the checks and balances to maintain steady blood flow and electrolyte balance present a great challenge to biochemists in their attempts to clarify the mechanisms involved at both molecular and cellular levels. In relation to the pathophysiology of hypertension, particularly essential hypertension, there is no question that the RAS plays a pivotal role. Although numerous mechanisms could explain its hypertensinogenic effects, no single mechanism can be identified as the major determinant at the present stage of our knowledge. However, there is an important consensus that the effect of Ang II is manifested slowly at even subpressor doses of Ang II through long-term effects involving remodelling of the cardiovascular and renal system.
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PMID:The renin-angiotensin system. 792 17

An association study of the polymorphism of the angiotensinogen gene, consisting of T-->C transition at nucleotide 704 in exon 2, with essential hypertension in the Japanese population was performed by restriction fragment length polymorphism (RFLP). The allele which contained the Tth 111-I restriction site in the presence of C transition was designated 'a' and the allele that lacked restriction site was designated 'A'. The frequency of aa genotype in our normotensive group was higher than the previously reported values in Caucasians. In spite of the high frequency of the aa genotype in Japanese, the aa genotype was significantly more frequent in 108 hypertensives than in 104 normotensive subjects compared with the two other genotypes (P = 0.009). These results suggested that this molecular variant of the angiotensinogen gene may be a preserved inherited predisposition for essential hypertension in various ethnic groups, including Caucasians and Japanese.
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PMID:Association analysis of a polymorphism of the angiotensinogen gene with essential hypertension in Japanese. 793 16


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