Angiotensin I-converting enzyme in human urine.

It was demonstrated that angiotensin I-converting enzyme was excreted in human urine. The mean activity of the enzyme in normal urine was found to be 0.38 +/- 0.04 (S.E.M.) units/day (n = 18) and the enzymic activity correlated well with the concentration of the excreted sodium (r = 0.76, p less than 0.005). Urinary angiotensin I-converting enzyme was partially purified. Three different molecular weights of enzyme (greater than 400 000, 290 000 and 140 000) were demonstrated by Sephadex G-200 gel filtration. The enzymic properties of these three enzymes were identical with those of angiotensin I-converting enzyme from human lung with regard to inhibitory effects (bradykinin potentiator c and Arg-Pro-Pro), Cl- dependency, pH optimum and KM value.     

Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a gender-specific association with hypertension

Human essential hypertension has a multifactorial origin and is caused by a delicate interaction between susceptibility genes and environmental factors. Candidate genes are selected from the renin-angiotensin system (RAS) and are physiologically implicated in blood pressure regulation. We investigated the association between insertion/deletion (I/D) polymorphism at the angiotensin-converting enzyme (ACE) locus and hypertension in a case-control study conducted in a population of Caucasians (175 females, 210 males). Case subjects were those with untreated borderline hypertension. A significant, moderate, male, gender-specific independent association between DD genotype and high blood pressure was found. Adjusted odds ratio (OR) was 2.0 (95% CI, 1.1 to 3.9; p=0.03) in the whole group and 2.5 (95% CI, 1.2 to 5.1; p=0.01) in the group truncated on the basis of age (< or = 50 years). Our findings support the hypothesis that ACE is a gender-specific candidate gene for hypertension.     

Angiotensin I-converting enzyme gene polymorphism in a Serbian population: a gender-specific association with hypertension

Human essential hypertension has a multifactorial origin and is caused by a delicate interaction between susceptibility genes and environmental factors. Candidate genes are selected from the renin-angiotensin system (RAS) and are physiologically implicated in blood pressure regulation. We investigated the association between insertion/deletion (I/D) polymorphism at the angiotensin-converting enzyme ( ACE ) locus and hypertension in a case-control study conducted in a population of Caucasians (175 females, 210 males). Case subjects were those with untreated borderline hypertension. A significant, moderate, male, gender-specific independent association between DD genotype and high blood pressure was found. Adjusted odds ratio (OR) was 2.0 (95% CI, 1.1 to 3.9; p = 0.03) in the whole group and 2.5 (95% CI, 1.2 to 5.1; p = 0.01) in the group truncated on the basis of age ( &#104 50 years). Our findings support the hypothesis that ACE is a gender-specific candidate gene for hypertension.     

Angiotensin I-converting enzyme in amniotic fluid

Angiotensin I-converting enzyme (ACE) is present in human amniotic fluid. We characterized the enzyme by both its antigenic and enzymatic properties. Using a specific direct radioimmunoassay, ACE was quantified and characterized in each of the 19 samples tested. Mean level was 136 +/- 83 ng/ml. Amniotic ACE completely crossreacted, like that in plasma and kidney, with antibodies raised against the lung enzyme. ACE activity in amniotic fluid averaged 8.7 +/- 5.6 microU/ml using Hip-His-Leu as substrate and was significantly correlated with ACE antigen levels. ACE was not associated with the cells or the free intracellular organelles in amniotic fluid, and the enzyme was present in soluble form. Angiotensinase activity and high levels of kininase activity were found in amniotic fluid. Inhibition studies with captopril and anti-human ACE antibodies suggest that angiotensinases and kininases other than ACE were also present. Because renin, mostly in inactive form, and angiotensinogen were also found in these amniotic fluids, it appears that a complete, although not fully activated, renin angiotensin system is present in amniotic fluid and fetal membranes during pregnancy.     

妊娠高血压综合征患者血管紧张素转换酶基因多态性研究

目的探讨血管紧张素转换酶(ACE)基因插入/缺失多态性与妊娠高血压综合征(PIH)的关系。方法应用聚合酶链反应(PCR)检测92例PIH患者及85名正常妊娠者的ACE基因多态性。结果PIH组ACE基因3种基因型频率分别为DD型44.6%、ID型33.7%、Ⅱ型21.7%,对照组ACE基因3种基因型频率分别为DD型18.8%、ID型40.0%、Ⅱ型41.2%;两组的DD基因型及D等位基因频率比较差异有显著性(P<0.05)。结论ACE基因的缺失多态性(DD)可能为妊高征发病的重要遗传因素之一。     

妊娠高血压综合征患者血管紧张素转换酶基因多态性研究

目的探讨血管紧张素转换酶（ACE）基因插入／缺失多态性与妊娠高血压综合征（PIH）的关系。方法应用聚合酶链反应（PCR）检测92例PIH患者及85名正常妊娠者的ACE基因多态性。结果PIH组ACE基因3种基因型频率分别为DD型44．6％、ID型33．7％、Ⅱ型21．7％,对照组ACE基因3种基因型频率分别为DD型18．8％、ID型40．0％、Ⅱ型41．2％;两组的DD基因型及D等位基因频率比较差异有显著性（P〈0．05）。结论ACE基因的缺失多态性（DD）可能为妊高征发病的重要遗传因素之一。     

Angiotensin converting enzyme gene polymorphism and glomerular filtration rate changes in type 2 diabetic patients

It has been suggested that an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene may be associated with diabetic nephropathy The aim of this study was to investigate whether an association exists between ACE I/D polymorphism and glomerular filtration rate (GFR) in type 2 diabetes mellitus. A total of 128 type 2 diabetic patients were included in the study with the following ACE genotype distribution: DD 40, ID 58,11 30. I/D polymorphism was determined by polymerase chain reaction (PCR). Mean GFR was not statistically different according to ACE genotype (DD: 89.9 +/- 28.1 ml/min, ID: 99.5 +/- 25.1 ml/min, II: 96.6 +/- 19.6 ml/min). There was no significant difference in genotype distribution in normo-, micro- and macroalbuminuric patients (DD:ID:II [%], normo- 35:46:19, micro-28:55:17, macro- 31:55:14). ACE I/D polymorphism does not seem to be associated with GFR in type 2 diabetic patients.     

Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients with breast cancer and effects on prognostic factors.

The aims of the present study were to investigate the distribution of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in breast cancer patients and the association between ACE genotypes and clinicopathologic features, as well as their effects on prognosis. We assessed the I/D polymophism of the ACE gene by using polymerase chain reaction from peripheral blood in breast cancer and healthy age-matched women. The clinicopathologic parameters of breast cancer patients were obtained from medical records. Of the 57 patients, 31 (54.4%) had DD, 24 (42.1%) had ID, and 2 (3.5%) had II genotypes. In control subjects, 33 (63.5%) had DD, 12 (23.1%) had ID, and 7 (13.4%) had II genotypes. The ID genotype was seen more commonly in breast cancer patients (p = .03). When the combination of ID and II genotypes was used as a reference group, the DD genotype was associated with negative hormone receptor status (p = .003), tumor size (p = .054), and lymph node involvement (p = .07) but not histologic high grade and c-erb B2 overexpression. These results suggest that the DD genotype may accompany poor prognostic factors and influence the tumor course.     

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.     

Angiotensin-converting enzyme gene polymorphism and erythropoietin requirement.

OBJECTIVES: To study the effect of angiotensin-converting enzyme (ACE) polymorphisms II, ID, and DD on erythropoietin (EPO) requirement in patients on continuous ambulatory peritoneal dialysis (CAPD) therapy. DESIGN: Retrospective observational study. SETTING: CAPD Unit, Royal London/St. Bartholomews Hospital, London, UK. PATIENTS: 46 patients on the transplant waiting list (age 20-70 years), on CAPD therapy for an average of 28 months, seen consecutively over a period of 3 months in the outpatients department. MAIN OUTCOME MEASURES: Primary end point: EPO dose requirement in different ACE genotypes. Secondary end points: C-reactive protein, ferritin, parathyroid hormone, Kt/V, duration of dialysis, folate, cause of renal failure, and whether or not patients were on ACE inhibitor therapy. RESULTS: There was a statistically significant difference (p < 0.05) in EPO requirement in the II/ID group compared to the DD group. The mean +/- standard error of EPO for the II/ID group was 144 +/- 15 U/kg/week, and for the DD group, 87 +/- 9 U/kg/week. The difference in EPO requirement could not be explained by age, C-reactive protein, ferritin, parathyroid hormone, Kt/V, duration of dialysis, folate, cause of renal failure, or whether or not patients were on ACE inhibitor therapy. CONCLUSION: In CAPD patients, ACE genotype has predictive value when determining the EPO dosage, as the III/ID genotype may be associated with a suboptimal response.     

Angiotensin II type 1 receptor antagonist versus angiotensin I-converting enzyme inhibitor in experimental renal diseases

Angiotensin II has an important role in the structural and functional regulation of the cardiovascular and renal systems. Blockade of the renin-angiotensin system can be achieved with angiotensin-converting enzyme (ACE) inhibitors and non-peptidic, orally active, angiotensin II type I receptor (AT1) antagonists. However, the question that has yet to be answered is whether ACE inhibitors and AT1 receptor antagonists have similar renoprotective effects in various experimental diseases. Although many studies have assessed the role of either ACE inhibitors or AT1 receptor antagonists, we have reviewed the literature comparing both types of blocker in the same experiment. In most models of hypertension or renal failure, both classes of blocker appear to have similar antihypertensive and renal profiles. In a few models, the influence of the ACE inhibitor on arterial pressure and/or renal function is more marked than that of the AT1 receptor antagonist. Even though the maximum dose-effect curve for each compound was not often carried out for the systemic haemodynamics and renal alterations, the difference between both classes of blocker, when observed, appeared to favour the participation of non-angiotensin II or non-AT1-mediated mechanisms. Among them are the stimulation of prostaglandin production, kinin accumulation, nitric oxide generation and modulation of endothelin or TGFbeta1 expression via direct or indirect pathways. Future experimental and probably human studies aimed at comparing angiotensin II receptor antagonists and ACE inhibitors, with respect to blood pressure and renal damage, should be designed with all these concerns in mind.     

The D allele of angiotensin I-converting enzyme gene insertion/deletion polymorphism is associated with the severity of atherosclerosis

BACKGROUND: Angiotensin II is produced primarily by angiotensin I-converting enzyme (ACE) within atherosclerotic lesions and ACE level in plaques correlates with the severity of vessel wall damage. Therefore, we investigated the possible association of ACE gene insertion/deletion (I/D) polymorphism and the severity of atherosclerosis, estimated on the basis of the number of coronary stenoses and critical arterial occlusions observed during coronary angiography. METHODS: The study cohort included 172 patients with angiographically confirmed premature coronary artery disease. The ACE gene I/D polymorphism was genotyped using a PCR method. RESULTS: The frequencies of DD genotype, D allele carrier-state (DD+ID genotypes) and the D allele increased with the number of stenoses in coronary vessels. D allele carriers (DD+ID genotypes) were more frequent in the subgroup of patients with stenoses in at least four coronary vessels than in other patients including subjects with one-, two- and three-vessel disease (97.4% vs. 74.4%, OR=13.05, 95% CI: 1.81-100.00, chi2=9.84, p=0.0017). Furthermore, the D allele was significantly more frequent in patients with critical arterial occlusions (>90%) than in subjects without critical stenoses (61.1% vs. 49.3%, chi2=9.84, p=0.023). CONCLUSIONS: The ACE I/D polymorphism influences individual differences in severity of coronary artery disease and the D allele promotes generation of numerous and critical atherosclerotic lesions.     

Angiotensin-converting enzyme gene polymorphism and premature coronary heart disease.

Since the initial report of the association of the deletion/insertion (D/I) polymorphism in the gene for angiotensin-converting enzyme (ACE) with myocardial infarction (MI), there has been considerable controversy. Some have found the D allele to be associated with MI, coronary heart disease (CHD) or other cardiac pathology, while others have not. In the present study 713 consecutive patients, < 50 years of age, documented prospectively with angiographic CHD (> 50% diameter stenosis of at least one coronary artery), with or without MI, were studied, along with 688 community control subjects, also < 50 years of age, selected randomly from the electoral rolls and without a history of CHD or MI. Genotyping was done by standard methods. Most of the subjects in both groups were Anglo-Celtic Caucasians (547 in the CHD group and 642 in the community group), and the report concerns primarily these subjects. ACE genotype distributions were not different between the Caucasian community control group and the CHD or the MI subgroups; the odds ratios and 95% confidence limits for the CHD group were 0.96 (0.73-1.27) for the D allele and 1.02 (0.80-1.31) for D homozygotes; for the MI group these values were 1.00 (0.83-1.20) and 0.99 (0.74-1.32) respectively. This negative result was supported in multivariate analysis accounting for conventional risk factors. There was a significant racial difference in ACE genotypes between Caucasians, Asians and Australian Aborigines in the CHD group (P < 0.001); for example, in this group, 158 of 540 (29%) Caucasians had the DD genotype compared with eight of 84 (10%) Aboriginals (P < 0.001) and six of 59 (10%) Asians (P = 0.002). Failure to account for such racial differences would have led to erroneous conclusions. In conclusion, we found no evidence that the D/I ACE gene polymorphism plays a role in the development of CHD or MI at an early age in a Western Australian Caucasian population. While this result refers uniquely to premature CHD and MI, and could be population specific, it is in general agreement with recent meta-analysis of the larger previous studies.     

Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.

Antihypertensive and cardioprotective effects of angiotensin I-converting enzyme (ACE) inhibitors are well established and have usually been attributed to the inhibition of angiotensin II (ANG)-mediated effects at vascular or ventricular (angiotensin type 1) AT(1) receptors. One other important mechanism involves ANG-induced interactions with the sympathetic nervous system, which might include alterations of cardiac catecholamine concentrations during ACE inhibition due to a modulation of monoamine oxidase (MAO) activity. Tissue catecholamines were studied in spontaneously hypertensive rats that were long-term treated with captopril (50 or 0.5 mg/kg/day), enalapril (10 or 0.1 mg/kg/day), an AT(1) receptor antagonist (candesartan-cilexetil, 3 mg/kg/day), or a calcium antagonist (mibefradil, 18 mg/kg/day). The kinetic parameters of MAO were then determined in vitro in the presence of ANG, captopril, enalaprilat, or candesartan. Noradrenaline and adrenaline contents were doubled in the left ventricle by captopril, enalapril, or candesartan independently of hypotensive potency but not in liver or cortex. In parallel, cardiac MAO activity was reduced by all doses of captopril (49/29%), enalapril (52/24%), or candesartan (38%). Mibefradil, which does not interact with the renin-angiotensin system, did not alter cardiac catecholamines or MAO activity when an equipotent antihypertensive dose was applied. In vitro MAO activity was not influenced by ANG, enalaprilat, or captopril at concentrations of up to 1 mM. It is concluded that diminished AT(1) receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT(1) antagonists had no effect on MAO activity in vitro. This action contributes to an increase in cardiac catecholamine content that may improve cardiac sympathetic control during therapy.     

Angiotensin I-converting enzyme inhibitors block protein kinase C epsilon by activating bradykinin B1 receptors in human endothelial cells

Angiotensin I-converting enzyme (ACE) inhibitors are widely used to treat patients with cardiovascular and kidney diseases, but inhibition of ACE alone does not fully explain the beneficial effects. We reported that ACE inhibitors directly activate bradykinin B1 receptor at the canonical Zn2+ binding site, leading to prolonged nitric oxide (NO) production in endothelial cells. Protein kinase C (PKC) epsilon, a novel PKC isoform, is up-regulated in myocardium after infarction, suggesting a role in the development of cardiac dysfunction. In cytokine-treated human lung microvascular endothelial cells, B1 receptor activation by ACE inhibitors (enalaprilat, quinaprilat) or peptide ligands (des-Arg10-Lys1-bradykinin, des-Arg9-bradykinin) inhibited PKC epsilon with an IC50 = 7 x 10(-9) M. Despite the reported differences in binding affinity to receptor, the two peptide ligands were equally active, even when inhibitor blocked the cleavage of Lys(1), thus the conversion by aminopeptidase. The synthetic undecapeptide (LLPHEAWHFAR) representing the binding site for ACE inhibitors on human B(1) receptors reduced PKC epsilon inhibition by enalaprilat but not by peptide agonist. A combination of inducible and endothelial NO synthase inhibitors, 1400W [N-(3(aminomethyl) benzyl) acetamidine dihydrochloride] and N omega-nitro-L-arginine (2 microM), significantly reduced inhibition by enalaprilat (100 nM), whereas the NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (100 microM) inhibited PKC epsilon activity just as the B1 ligands did. In conclusion, NO generated by B1 receptor activation inhibits PKC epsilon.