Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene coding for the main components of the renin-angiotensin system have been characterized and localized: angiotensinogen (AGT, chromosome 1q42), renin (REN, chromosome 1), angiotensin I-converting enzyme (ACE, chromosome 17), angiotensin II receptors (AT1R, chromosome 3 and AT2R, chromosome X). A positive linkage and association have been found between AGT and essential hypertension. M235T is also associated with plasma AGT concentration. In vitro studies suggest that a polymorphism (G-6A) which is in complete linkage disequilibrium with M235T and which is located in the promoter close to the start of transcription might explain this association with high blood pressure. The ACE I/D polymorphism explains about 30 to 40 per cent of the variance of plasma ACE levels. Although the ACE gene itself does not seem to play a role in blood pressure level, the corresponding chromosomal region has been linked to blood pressure in both spontaneously hypertensive rats and humans. In tissues, an increased ACE activity may explain the association between the ACE I/D polymorphism and coronary heart disease, left ventricular hypertrophy, neointimal proliferation in vessels and progression of diabetic and IgA nephropathy.
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PMID:[Genetic polymorphisms in the renin-angiotensin system]. 977 26

The classically recognized functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors. Whereas man possesses a single AT1 receptor, there are two AT1 receptor isoforms in rodents (AT1A and AT1B) that are products of separate genes (Agtr1a and Agtr1b). We have generated mice lacking AT1B (Agtr1b -/-) and both AT1A and AT1B receptors (Agtr1a -/-Agtr1b -/-). Agtr1b -/- mice are healthy, without an abnormal phenotype. In contrast, Agtr1a -/-Agtr1b -/- mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt-/-) and angiotensin-converting enzyme-deficient (Ace -/-) mice that are unable to synthesize angiotensin II. Agtr1a -/-Agtr1b -/- mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a -/- Agtr1b -/- mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT2-receptor signaling. In summary, our studies suggest that both AT1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT1 receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT1 receptors to mediate physiological functions of the renin-angiotensin system.
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PMID:Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. 986 Sep 97

The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I-converting enzyme (ACE) gene [4656(CT)(2/3)], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. B(max) and K(D) values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT)(2/3) variant with plasma ACE levels was observed (P<0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (P=0.017), but no significant effect was detectable with the other AGT polymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (P=0.02). No genotype effect of the AT1R A1166C polymorphism was detected either on the B(max) or the K(D) value of the Ang II receptors on platelets.
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PMID:Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. 1048 88

Recent findings suggest that the ovarian renin-angiotensin system regulates ovarian function through the paracrine/autocrine actions of angiotensin (Ang) II. The aims of this study were to investigate 1) the endothelial cell capacity to convert Ang I to Ang II, 2) the effects of endocrine and paracrine/autocrine factors on Ang II production in microvascular endothelial cells (MVE) derived from the developing corpora lutea (CL), and 3) the relationship between Ang II peptide concentration and expression of mRNA for angiotensin type 1 and 2 receptors (ATR1 and AT2R) in the bovine CL at different stages of the estrous cycle. When Ang I was added to the MVE at a concentration of 10(-9) M, it was converted to Ang II (21%). The production of Ang II from Ang I time-dependently rose for 24 h. Addition of captopril (an inhibitor of Ang-converting enzyme [ACE]) to the MVE cultures significantly inhibited Ang II production from 6 h to 24 h (P < 0.05). Addition of estradiol-17beta (E(2)) + vascular endothelial growth factor and E(2) + basic fibroblast growth factor to MVE cultures increased Ang II production, whereas E(2) or growth factors alone had no effect. Specific transcription for AT1R and AT2R was detected in bovine CL and MVE. There were no significant changes in Ang II tissue concentration or AT1R mRNA expression using reverse transcription-polymerase chain reaction during the estrous cycle. In contrast, AT2R mRNA expression decreased during the midluteal phase (P < 0.05) and increased to the highest level during the late luteal phase (P < 0.05). Results demonstrated that Ang II is generated from Ang I in MVE isolated from the developing bovine CL, indicating that MVE have ACE activity. In addition, mRNA expression for Ang II receptors was detected in the bovine CL and the luteal MVE. These results suggest that Ang II is produced by actions of the local renin-angiotensin system, at least in part, on MVE in the bovine CL, and that this peptide may be involved in the regulation of luteal function during early development and luteolysis.
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PMID:Regulation of angiotensin II production and angiotensin receptors in microvascular endothelial cells from bovine corpus luteum. 1061 Oct 81

Vascular disease is a multifactorial disease that involves atherosclerotic and thrombotic factors. Genetic polymorphisms have been associated with myocardial infarction and angina pectoris. The aim of the present study was to assess the relationship between some genetic polymorphisms and myocardial infarction (MI) or vasospastic angina pectoris in a population from southern France. Genetic polymorphisms of the renin angiotensin system (the D/I polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor [AT1R]) and of haemostatic factors (the -675 4G/5G polymorphism of the plasminogen-activator inhibitor 1[PAI-1] gene, and the G to T common point mutation in exon 2, codon 34 of the Factor XIII A-subunit gene) were examined. We assessed the genotype distribution in consecutive coronary artery disease (CAD) patients with MI (n = 201) and vasospastic angina pectoris (n = 43) and in 244 healthy controls comparable in age, sex, body mass index and total cholesterol level. The genotype distribution of AT1R polymorphism was significantly different between controls and patients, the prevalence of the C allele carriers being higher in patients with MI after the age of 45 than in control individuals (61 vs 45%, p <0.01), leading to an odds ratio (OR) of 2 (CI: 1.2-3.4). When looking at the group of patients with vasospastic angina the difference was even higher (76 vs 45%, p <0.01) yielding an OR of 4.3 (CI: 1.4-17.4). Genotype distributions of ACE, PAI-1 and Factor XIII polymorphisms were similar in patients and in controls. This study is in favor of a role of ATIR gene polymorphism in myocardial infarction and vasospastic angina.
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PMID:Genetic polymorphisms and coronary artery disease in the south of France. 1073 75

A multilocus assay was used to genotype up to 27 variable sites in 15 genes in French and Italian, presumed to be healthy populations (n=1480, n=162, respectively). These genes are involved in lipid metabolism (APOE, APOB, APOC3, CETP, LPL, PON), homocysteine metabolism (CBS, MTHFR), blood viscosity (Fibrinogen, FV), platelet aggregation (GpIIIa), leukocyte adhesion (SELE), and renin-angiotensin system (AT1R, ACE, AGT). Allele frequencies for all the markers were compared between the two populations. Five allele frequencies differed between the two European countries: APOB 71Ile (p < 0.001), SELE 98T (p < 0.001), SELE 128Arg (p < or = 0.01), APOE E4 (p < or = 0.01) and MTHFR 677T (p < or = 0.01), suggesting the existence of a north-south gradient in European allele frequencies. The other allele frequencies : APOC3 -482T, -455C, 1100T, 3175G, 3206G; LPL -93G, 9Asn, 291Ser; CETP 405Val; PON 192Arg; ACE Del; AGT 235Thr; AT1R 1166C; CBS 278Thr, GpIIIa P1A2; Fibrinogen -455A, FV 506Gln and SELE 554Phe, were similar between the two populations. They were also similar to those observed in other European countries.
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PMID:Candidate gene polymorphisms in cardiovascular disease: a comparative study of frequencies between a French and an Italian population. 1134 49

Arterial hypertension is a major risk factor for microangiopathic diabetic complications and associated with an increased cardiovascular morbidity and mortality. An intensified antihypertensive treatment reduces microangiopathic complications and cardiovascular morbidity and mortality in diabetic patients. Even in normotensive type 1 and type 2 diabetic patients, the treatment with ACE inhibitors may prevent the later development of diabetic nephropathy. Treatment with ACE inhibitors increases the concentrations of bradykinin, which is responsible for the side effects such as cough and urticaria in some patients. On the other hand, bradykinin may have beneficial intrarenal effects decreasing the intraglomerular pressure. The novel angiotensin II receptor type 1 antagonists do not influence the bradykinin concentrations and seem to be tolerated by patients suffering from chronic cough with ACE inhibitor therapy. It is still unclear whether the different intrarenal effects are of clinical relevance in the long-term treatment of diabetic patients. In studies with diabetic animals the nephroprotective effects of ACE inhibitors and angiotensin II type 1 receptor antagonists are comparable. It was shown that glucose and lipid metabolism is not influenced by treatment with angiotensin II type 1 receptor antagonists. Further compared to Felodipine the reduction of urinary albumin excretion rate (UAER) was more pronounced by Losartane in Chinese type 2 diabetic patients. Short-term studies directly comparing the renal effects of ACE inhibitors with AT II type 1 receptor antagonists revealed similar reduction of blood pressure and albumin excretion rate in patients with diabetic nephropathy, so a combination of both substances might be useful. Data from ongoing long-term trials are still missing. Further, it is unknown whether different phenotypes of the ACE gene (DD, II polymorphism) require different therapeutic options. In conclusion, treatment with angiotensin II receptor antagonists is well-tolerated and has no adverse effects on metabolic control in diabetic patients. The beneficial effect on microangiopathic complications however has to be proven in randomized long-term studies in direct comparison with ACE inhibitors, which were clearly shown to delay the development and progression of diabetic nephropathy.
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PMID:[Angiotensin II type-1 receptor antagonists and diabetes mellitus]. 1145 Jan 65

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT1R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall > or = 10 mm Hg systolic or > or = 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7+/-8.1/3.3+/-5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT1R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.
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PMID:Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism? 1146 54

We have previously shown correlations between cardiovascular risk factors such as blood pressure (BP), sympathetic nervous system activity, lipids and insulin resistance in young men with elevated screening BP. In the present study we aimed to: (1) compare the genotype distribution and allele frequencies of 11 polymorphisms in seven candidate genes for BP regulation in healthy 21-year-old Caucasian men, between 18 men with normal and 67 men with high screening BP, and (2) evaluate the effect of these polymorphisms in candidate genes on casual BP, BP responses to mental stress or catecholamines and metabolic parameters including insulin sensitivity. There were no differences in genotype distributions or allele frequencies between the subjects with normal and those with high screening BP. Insulin sensitivity was significantly higher in GG homozygotes in the G-261A polymorphism at the alpha 2A-adrenergic receptor (alpha(2A)AR) locus compared to GA heterozygotes (p = 0.007). Subjects who were homozygous both GG in the G-261A polymorphism at the alpha(2A)AR locus and GlyGly in the Arg16Gly polymorphism at the beta2-adrenergic (beta2AR) receptor loci had significantly higher insulin sensitivity and lower catecholamine levels during mental stress than subjects with other genotypes. Subjects who were II homozygous at the angiotensin converting enzyme (ACE) locus and AA homozygous at the angiotensin type I receptor (AT1R) locus had lower BP and a better lipid profile than the rest of the group. Thus, in this explorative study, we report an association between insulin sensitivity and a polymorphism at the alpha(2A)AR locus. We suggest the presence of gene-gene interactions in the renin-angiotensin system and the sympathetic nervous system.
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PMID:Polymorphisms in candidate genes for blood pressure regulation in young men with normal or elevated screening blood pressure. 1146 65

Plasminogen activator inhibitor type-1 (PAI-1) is known to contribute to thrombus formation and to the development and the clinical course of acute and chronic cardiovascular disease, as well as of other arterial and venous thromboembolic diseases. Recently, an important role of elevated pretreatment levels of PAI-1 for failure of thrombolytic therapy of acute myocardial infarction has been discussed. PAI-1 plasma levels depend on the one hand on gene regulation but are related on the other hand to known risk factors of atherosclerosis like insulin resistance, diabetes or hypertriglyceridemia, respectively. Furthermore, an activated renin-angiotensin-aldosterone system (RAAS) significantly contributes to the upregulation of PAI-1 concentration via a receptor-mediated mechanism. In accordance to the known mechanisms of regulation of PAI-1 plasma levels, the use of specific agents like antidiabetic drugs, fibrates, statins, ACE inhibitors and angiotensin II type-1 receptor-blockers may contribute to the downregulation of circulating PAI-1 and, therefore, increase the fibrinolytic capacity and consecutively counteract the thrombotic tendency. To further improve the efficacy of thrombolytic therapy, a PAI-1 resistant variant of t-PA, TNK-t-PA, has been developed and is now available for acute myocardial infarction.
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PMID:Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report 2001. 1156 64


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