Higher Angiotensin-converting Enzyme Activity Research Articles

Mathematical modelling of the influence of ACE I/D polymorphism on blood pressure and antihypertensive therapy

The angiotensin-converting enzyme (ACE) gene (ACE) insertion/deletion (I/D) polymorphism raises the possibility of personalising ACE inhibitor therapy to optimise its efficiency and reduce side effects in genetically distinct subgroups. However, the extent of its influence among these subgroups is unknown. Therefore, we extended our computational model of blood pressure regulation to investigate the effect of the ACE I/D polymorphism on haemodynamic parameters in humans undergoing antihypertensive therapy. The model showed that the dependence of blood pressure on serum ACE activity is a function of saturation and therefore, the lack of association between ACE I/D and blood pressure levels may be due to high ACE activity in specific populations. Additionally, in an extended model simulating the effects of different classes of antihypertensive drugs, we explored the relationship between ACE I/D and the efficacy of inhibitors of the renin–angiotensin–aldosterone system. The model predicted that the response of cardiovascular and renal parameters to treatment directly depends on ACE activity. However, significant differences in parameter changes were observed only between groups with high and low ACE levels, while different ACE I/D genotypes within the same group had similar changes in absolute values. We conclude that a single genetic variant is responsible for only a small fraction of heredity in treatment success and its predictive value is limited.

Optimization of Extraction Process and Activity of Angiotensin-Converting Enzyme (ACE) Inhibitory Peptide from Walnut Meal.

In order to further realize the resource reuse of walnut meal after oil extraction, walnut meal was used as raw material to prepare polypeptide, and its angiotensin-converting enzyme (ACE) inhibitory activity was investigated. The ACE inhibitory peptides were prepared from walnut meal protein by alkaline solution and acid precipitation. The hydrolysis degree and ACE inhibition rate were used as indexes to optimize the preparation process by single-factor experiment and response surface method. The components with the highest ACE activity were screened by ultrafiltration, and their antioxidant activities were evaluated in vitro. The effect of gastrointestinal digestion on the stability of walnut peptide was analyzed by measuring molecular weight and ACE inhibition rate. The results showed that the optimal extraction conditions were pH 9.10, hydrolysis temperature 54.50 °C, and hydrolysis time 136 min. The ACE inhibition rate of walnut meal hydrolysate (WMH) prepared under these conditions was 63.93% ± 0.43%. Under the above conditions, the fraction less than 3 kDa showed the highest ACE inhibitory activity among the ACE inhibitory peptides separated by ultrafiltration. The IC50 value of scavenging ·OH free radical was 1.156 mg/mL, the IC50 value of scavenging DPPH free radical was 0.25 mg/mL, and the IC50 value of scavenging O2- was 3.026 mg/mL, showing a strong total reducing ability. After simulated gastrointestinal digestion in vitro, the ACE inhibitory rate of walnut peptide decreased significantly, but it still maintained over 90% ACE inhibitory activity. This study provides a reference for the application of low-molecular-weight walnut peptide as a potential antioxidant and ACE inhibitor.

Human Tissue Angiotensin Converting Enzyme (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and Heart.

Objective: Inhibitors of the angiotensin converting enzyme (ACE) are the primarily chosen drugs to treat heart failure and hypertension. Moreover, an imbalance in tissue ACE/ACE2 activity is implicated in COVID-19. In the present study, we tested the relationships between circulating and tissue (lung and heart) ACE levels in men. Methods: Serum, lung (n = 91) and heart (n = 72) tissue samples were collected from Caucasian patients undergoing lung surgery or heart transplantation. ACE I/D genotype, ACE concentration and ACE activity were determined from serum and tissue samples. Clinical parameters were also recorded. Results: A protocol for ACE extraction was developed for tissue ACE measurements. Extraction of tissue-localized ACE was optimal in a 0.3% Triton-X-100 containing buffer, resulting in 260 ± 12% higher ACE activity over detergent-free conditions. SDS or higher Triton-X-100 concentrations inhibited the ACE activity. Serum ACE concentration correlated with ACE I/D genotype (II: 166 ± 143 ng/mL, n = 19, ID: 198 ± 113 ng/mL, n = 44 and DD: 258 ± 109 ng/mL, n = 28, p < 0.05) as expected. In contrast, ACE expression levels in the lung tissue were approximately the same irrespective of the ACE I/D genotype (II: 1423 ± 1276 ng/mg, ID: 1040 ± 712 ng/mg and DD: 930 ± 1273 ng/mg, p > 0.05) in the same patients (values are in median ± IQR). Moreover, no correlations were found between circulating and lung tissue ACE concentrations and activities (Spearman’s p > 0.05). In contrast, a significant correlation was identified between ACE activities in serum and heart tissues (Spearman’s Rho = 0.32, p < 0.01). Finally, ACE activities in lung and the serum were endogenously inhibited to similar degrees (i.e., to 69 ± 1% and 53 ± 2%, respectively). Conclusion: Our data suggest that circulating ACE activity correlates with left ventricular ACE, but not with lung ACE in human. More specifically, ACE activity is tightly coordinated by genotype-dependent expression, endogenous inhibition and secretion mechanisms.

An evaluation of renin-angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes.

Youth with type 2 diabetes (T2D) have high rates of obesity, hypertension and suboptimal glycemic control. We hypothesized that renin-angiotensin system (RAS) activation is present in youth with T2D and associated with poor glycemic control and renal outcomes. Cross-sectional analysis of 183 youth with T2D and 100 controls from the Improving renal Complications in Adolescents with T2D through REsearch cohort. Diabetes youth stratified by urine albumin:creatinine ratio (ACR) < or ≥2 mg/mmol. RAS levels measured with enzyme-linked immunosorbent assay (ELISA) and enzyme activities by synthetic substrates. In T2D, levels log transformed and Tobit linear regressions evaluated for associations with hemoglobin A1c (HbA1c), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), ACR. Youth were 14 to 15 years, with diabetes duration 1.7 to 1.8 years; 21.3% albuminuria. Serum: differences in plasma renin activity (<0.0001), and angiotensin converting enzyme (ACE) activity (P = .003) in T2D vs controls. Urine: higher ACE activity and ACE2 protein/activity (all P < .0001) in T2D, higher levels in T2D with albuminuria. Multivariable regressions: higher serum ACE activity (ß = 0.03, SE 0.01;P < .01), urine ACE activity (ß = 0.44, SE 0.18;P < .01), ACE2 (ß = 0.51, SE 0.19;P < .01) positively associated with HbA1c; urine angiotensinogen (AGT) negatively associated (ß = -0.28 [SE 0.06;P < .01]). Higher serum aldosterone (ß = 0.11 [SE 0.04;P < .01]) and urine AGT (ß = 0.32 [SE 0.07;P < .01]) significantly associated with ACR and urine ACE2 (ß = 0.21 [SE 0.13;P < .03]). No associations between RAS markers and eGFR/MAP. RAS activation present in youth with T2D and associated with higher HbA1c. Higher serum aldosterone and urine AGT associated with albuminuria. The prognostic significance of the combined effect of glycemia and RAS activation on renal outcomes requires additional investigation.

Lower left ventricular ejection fraction and higher serum angiotensin-converting enzyme activity are associated with histopathological diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis

BackgroundThe histopathological diagnosis of cardiac sarcoidosis (CS) is challenging because of sampling error in endomyocardial biopsy (EMB) and the determinants of positive EMB are unclear. Reduced left ventricular ejection fraction (LVEF) is a simple parameter of the extent of myocardial damage, and higher serum angiotensin-converting enzyme (ACE) activity would indicate the spread of disease activity in CS patients. Thus, we sought to examine whether these parameters are related to the histopathological diagnosis of CS by EMB. MethodsA total of 94 consecutive clinically diagnosed CS patients between August 1986 and March 2019 who were admitted to two academic hospitals were examined. We determined EMB as positive if non-caseating epithelioid granulomas were confirmed in the myocardial tissue. Patients were divided into two groups according to positive (n = 37) and negative (n = 57) EMB. We assessed the relationship between LVEF, serum ACE activity and positive EMB. ResultsMultivariable analysis revealed that both LVEF and serum ACE were independently associated with positive EMB (OR 0.83, 95% CI 0.70–0.99; OR 1.39, 95% CI 1.02–1.90, respectively). Moreover, patients with both lower LVEF (<37%, median) and higher ACE activity (≥13.5 IU/L, median) had the highest frequency of positive EMB (p = .003). The combination of lower LVEF and higher serum ACE showed better specificity (91.2%) and positive predictive value (73.7%) than either LVEF or serum ACE alone for positive EMB. ConclusionsLower LVEF and higher serum ACE activity were associated with positive EMB, suggesting that these parameters might be useful for predicting positive EMB in CS patients.

Relationship of quadriceps muscle power and optimal shortening velocity with angiotensin-converting enzyme activity in older women.

BackgroundThe goal of this study was to assess whether angiotensin-converting enzyme (ACE) activity is related to muscle function (strength, power and velocity), as well as to assess if ACE inhibitors (ACEIs) and other angiotensin system blocking medications (ASBMs) influence muscle performance in elderly women.Subjects and methodsNinety-five community-dwelling elderly women took part in this study. Anthropometric data, blood ACE activity analysis, maximum power (Pmax) and optimal shortening velocity (υopt) of the knee extensor muscles, handgrip strength, physical activity (PA) and functional performance were measured.ResultsWomen taking ACEI were on average almost 2 years older than the women who did not take ACEI. They took more medicines and were also characterized by significantly lower level of ACE, but they did not differ in terms of PA level, results of functional performance and parameters characterizing muscle functions. No correlations of ACE activity with Pmax and handgrip strength, as well as with PA or functional performance were found. Higher ACE activity was connected with lower υopt for women who did not take any ASBMs (rho =−0.37; p=0.01).ConclusionSerum ACE activity was not associated with muscle strength, power and functional performance in both ASBM users and nonusers, but was associated with optimal shortening velocity of quadriceps muscles in older women. Further prospective studies are needed to assess if ACEIs or other ASBMs may slow down the decline in muscle function and performance.

Modification of epigenetic patterns in low birth weight children: importance of hypomethylation of the ACE gene promoter.

There is a growing body of evidence that epigenetic alterations are involved in the pathological mechanisms of many chronic disorders linked to fetal programming. Angiotensin-converting enzyme (ACE) appears as one candidate gene that brings new insights into the epigenetic control and later development of diseases. In this view, we have postulated that epigenetic modifications in the ACE gene might show different interactions between birth weight (BW), blood pressure levels, plasma ACE activity and ACE I/D polymorphism. To explore this hypothesis, we performed a cross-sectional study to evaluate the DNA methylation of 3 CpG sites using pyrosequencing within the ACE gene promoter of peripheral blood leukocytes from 45 LBW children compared with 70 NBW children. Our results have revealed that LBW children have lower methylation levels (P<0.001) in parallel with a higher ACE activity (P = 0.001). Adjusting for prematurity, gender, age, body mass index, and family history of cardiovascular disease did not alter these findings. We have also performed analyses of individual CpG sites. The frequency of DNA methylation was significantly different at two CpG sites (site 1: nucleotide position +555; and site 3: nucleotide position +563). In addition, we have found a significant inverse correlation between degree of DNA methylation and both ACE activity (P<0.001) and systolic blood pressure levels (P<0.001). We also observed that the methylation level was significantly lower in LBW children who are carriers of the DD genotype compared to NBW children with DD genotype (P<0.024). In conclusion, we are able to demonstrate that the hypomethylation in the 3 CpG sites of ACE gene promoter is associated with LBW in 6 to 12 year-old children. The magnitude of these epigenetic changes appears to be clinically important, which is supported by the observation that discrete changes in DNA methylation can affect systolic blood pressure and ACE protein activity levels.

The biological activity of fermented dairy products obtained by kombucha and conventional starter cultures during storage

The effects of kombucha inoculum as a new starter culture for milk fermentation were investigated, during 14 days of storage. The antioxidant capacity, angiotensin converting enzyme (ACE) inhibitory activity, degree of proteolysis (DP), content of vitamin C as well as sensory properties of kombucha fermented milk, were analysed and compared with fermented milk products obtained by commercial probiotic (ABT-10) and yoghurt (YF-L812) starter cultures. The kombucha fermented milk product (K) showed similar trend of changes in pH, DP and sensory properties as products obtained by probiotic (P) and yoghurt (Y) starters. Significant ACE inhibitory was determined in all fermented products, which increased during storage. Kombucha product had the highest ACE activity (63.43%) at the end of storage compared with probiotic and yoghurt products. In all products, higher 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) than 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity was determined, while both activities slightly decreased during storage. Based on estimated biological activity the kombucha product can be considered as an innovative fermented dairy product suitable for human nutrition.

ACE genotype, phenotype and all-cause mortality in different cohorts of patients with type 1 diabetes

Carrying the D-allele of the angiotensin-converting enzyme (ACE) I/D polymorphism and high ACE activity are prognostic factors in diabetic nephropathy, which predicts mortality in type 1 diabetes. We studied the association between the ACE D-allele and ACE phenotype and long-term all-cause mortality in three single-institution outpatient cohorts. Genotype-based analyses were performed in 269 patients from Hillerød Hospital (HIH) (follow-up: 12 years) and in 439 patients with diabetic nephropathy and 437 patients with persistent normoalbuminuria from the Steno Diabetes Center (SDC) (follow-up: 9.5 years). Patients not on renin-angiotensin system (RAS)-blocking treatment were included in analyses of serum ACE activity (HIH: n = 208) and plasma ACE concentration (SDC: n=269). In the HIH cohort, carrying a D-allele was associated with excess mortality (hazard ratio (HR) = 4.0 (95% confidence interval (CI) 1.0-16)), but not in the SDC cohorts. At HIH, serum ACE activity was associated with excess mortality (HR=1.04 (95% CI 1.0-1.1 per unit increase)), but in the SDC cohort plasma ACE concentration was not. In unselected patients with type 1 diabetes, carrying the ACE D-allele and high spontaneous serum ACE activity were associated with 12-year excess mortality. These findings could not be reproduced in two other cohorts with persistent normoalbuminuria or diabetic nephropathy.

The association between D allele of the ACE gene and power performance in Polish elite athletes

ACE gene that codes for angiotensin converting enzyme (ACE) is characterised by the presence (insertion, I allele) or the absence (deletion, D allele) of a 287-bp fragment. The longer I allele initiates lower enzyme activity, and is associated with enhanced endurance performance. The shorter variant (D allele) is associated with higher ACE activity and increased angiotensin II levels; thus, this allele would theoretically favour performance in power or strength-oriented exercise tasks. We decided to test the hypothesis that the D allele might represent a genetic element that benefits power performance in elite Polish athletes. The ACE genotypes were established using PCR amplification for 100 Polish power athletes of the highest nationally competitive standard and 354 sedentary volunteers. The genotype distribution amongst the whole cohort of athletes (13.0% II, 48.0% ID, 39.0% DD) was significantly different from that amongst controls (20.9% II, 51.7% ID, 27.4% DD; P = 0.043); a significant excess of the D allele being noted in the power athlete group (63.0% versus 53.2%, P = 0.014). The lowest frequencies of the D allele were observed in ‘sub-elite’ athletes (53.3%), while in ‘elite’ and ‘top-elite’ athletes an increasing trend of D allele frequency was found (68.1% and 77.8%, respectively) that remained statistical significant when compared to controls (P = 0.016 and P = 0.004, respectively). Our study demonstrates a significant positive association between top-level Polish power athletes and the ACE D allele, distinguishing it as one of the genetic factors that contribute to the establishment of a strength phenotype. Le gène ACE code l’enzyme de conversion de l’angiotensine (ACE) ; il se caractérise par la présence (allèle I) ou la délétion (allèle D) d’un fragment de 287 paires de bases. L’allèle I est lié à l’activité enzymatique plus basse de l’enzyme et souvent associé à l’augmentation des performances en endurance. À l’inverse, l’allèle D est lié à une augmentation de l’activité de l’ACE et un niveau plus élevé de l’angiotensine II ; la présence de cet allèle semble favoriser les capacités physiques de type développement de force. L’objectif de cette étude a été de vérifier l’hypothèse selon laquelle la présence de l’allèle D pourrait être un facteur génétique favorisant les performance en force chez des sportifs polonais de haut niveau. Détermination des génotypes des 100 meilleurs athlètes polonais concourant dans des disciplines de force et chez 354 volontaires sains, non sportifs. La répartition des génotypes dans le groupe des sportifs (13,0 % II, 48,0 % ID, 39,0 % DD) était différente de celle du groupe des sédentaires (20,9 % II, 51,7 % ID, 27,4 % DD ; p = 0,043) ; on a constaté la prédominance de l’allèle D dans le groupe des sportifs de force (63,0 % versus 53,2 %, p = 0,014). La fréquence de l’allèle D est moins élevée dans le groupe dit « élite-B » (53,3 %). Dans les groupes dits « élite-A » et « top-élite » on a constaté une tendance à l’augmentation des fréquences de l’allèle D (respectivement, 68,1 % et 77,8 %), qui diffèrent de la fréquence observée dans le groupe des sédentaires (respectivement, p = 0,016 et p = 0,004). Ces résultats témoignent de l’existence d’une association probable entre la présence de l’allèle D du gène ACE et les performances en force chez des sportifs de haut niveau.

Dopaminergic neuroprotection of hormonal replacement therapy in young and aged menopausal rats: role of the brain angiotensin system

There is a lack of consensus about the effects of the type of menopause (surgical or natural) and of oestrogen replacement therapy on Parkinson's disease. The effects of the timing of replacement therapy and the female's age may explain the observed differences in such effects. However, the mechanisms involved are poorly understood. The renin-angiotensin system mediates the beneficial effects of oestrogen in several tissues, and we have previously shown that dopaminergic cell loss is enhanced by angiotensin via type 1 receptors, which is activated by ageing. In rats, we compared the effects of oestrogen replacement therapy on 6-hydroxydopamine-induced dopaminergic degeneration, nigral renin-angiotensin system activity, activation of the nicotinamide adenine dinucleotide phosphate oxidase complex and levels of the proinflammatory cytokine interleukin-1β in young (surgical) menopausal rats and aged menopausal rats. In young surgically menopausal rats, the renin-angiotensin system activity was higher (i.e. higher angiotensin converting enzyme activity, higher angiotensin type-1 receptor expression and lower angiotensin type-2 receptor expression) than in surgically menopausal rats treated with oestrogen; the nicotinamide adenine dinucleotide phosphate oxidase activity and interleukin-1β expression were also higher in the first group than in the second group. In aged menopausal rats, the levels of nigral renin-angiotensin and nicotinamide adenine dinucleotide phosphate oxidase activity were similar to those observed in surgically menopausal rats. However, oestrogen replacement therapy significantly reduced 6-hydroxydopamine-induced dopaminergic cell loss in young menopausal rats but not in aged rats. Treatment with oestrogen also led to a more marked reduction in nigral renin-angiotensin and nicotinamide adenine dinucleotide phosphate oxidase activity in young surgically menopausal rats (treated either immediately or after a period of hypo-oestrogenicity) than in aged menopausal rats. Interestingly, treatment with the angiotensin type-1 receptor antagonist candesartan led to remarkable reduction in renin-angiotensin system activity and dopaminergic neuron loss in both groups of menopausal rats. This suggests that manipulation of the brain renin-angiotensin system may be an efficient approach for the prevention or treatment of Parkinson's disease in oestrogen-deficient females, together with or instead of oestrogen replacement therapy.

High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes

Aims/hypothesis. High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. Methods. A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. Results. ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2-fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. Conclusion. In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders.

RatAceallele variation determines susceptibility to AngII-induced renal damage

Ace b/l polymorphism in rats is associated with differential tissue angiotensin-converting enzyme (ACE) expression and activity, and susceptibility to renal damage. Same polymorphism was recently found in outbred Wistar rat strain with b allele accounting for higher renal ACE, and provided a model for studying renin-angiotensin-aldosterone system (RAAS) response behind the innate high or low ACE conditions. We investigated the reaction of these alleles on chronic angiotensin II (AngII) infusion. Wistar rats were selected to breed male homozygotes for the b (WU-B) or l allele (WU-L) (n = 12). For each allele, one group (n = 6) received AngII infusion via an osmotic minipump (435 ng/kg/min) for 3 weeks. The other group (n = 6) served as a control. WU-B had higher ACE activity at baseline then WU-L. Interestingly, baseline renal ACE2 expression and activity were higher in WU-L. AngII infusion induced the same increase in blood pressure in both genotypes, no proteinuria, but caused tubulo-interstitial renal damage with increased α-SMA and monocyte/macrophage influx only in WU-B (p < 0.05). Low ACE WU-L rats did not develop renal damage. AngII infusion causes proteinuria-independent renal damage only in rats with genetically predetermined high ACE while rats with low ACE seemed to be protected against the detrimental effect of AngII. Differences in renal ACE2, mirroring those in ACE, might be involved.

Polymorphisms of the angiotensin converting enzyme gene in relation to intrauterine growth restriction

The aim of this case-control study was to explore the relation between maternal and infant angiotensin converting enzyme (ACE) activity and its genotypes in uncomplicated term pregnancies (> or =37 weeks) and pregnancies with growth-restricted infants (birthweight at or below the 5th centile). Venous cord bloods and maternal venous samples were obtained for serum ACE activity and ACE genotype. Growth-restricted infants (< or =5th centile) were more likely to be of the DD genotype compared to appropriately grown infants (42 vs. 13%, p = 0.003). There was no significant difference in the frequency of the maternal DD genotype between the two groups (33 vs. 22%, p = 0.43) and similarly no significant differences in the maternal or fetal ACE activities. Within the intrauterine growth restriction (IUGR) group, infants of the DD genotype had higher ACE activity compared to appropriately grown infants (p = 0.03). In conclusion, the DD genotype of the ACE gene appears to be associated with fetal growth and may be a factor in the increased risk of adult onset chronic diseases among growth-restricted infants.

ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men

Angiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men. 1486 out of 2,000 community-dwelling Chinese men aged 65years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism. Subjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P=0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49ng/ml in non-users, P=0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3beta,17beta-diol (0.68 versus 0.72ng/ml in non-users; 552.4 versus 624.1pg/ml respectively, both P values <0.05). Serum testosterone and estradiol were not significantly changed. ACE inhibitor use was associated with lower serum DHEA in older men.

Influence of lipopolysaccharide on angiotensin converting enzyme activity expressed by human umbilical vein endothelial cells in culture

The activity of angiotensin converting enzyme (ACE) released into the culture medium of human umbilical cord vein endothelial cells in culture (HUVEC) for 24-hour incubation with or without various serotypes of lipopolysaccharide (LPS) was unchanged. ACE activity, however, in cell lysate or monolayer HUVEC after 24-hour incubation of various serotypes of LPS except LPS from E. coli, 026:B6, showed significant decrease, compared with no LPS treatment. Cell lysate contained much higher ACE activity than monolayer HUVEC after 24-hour incubation with or without LPS. These findings give rise to speculation that ACE or ACE-like substance might be located not only on the luminal surface, but also in cytoplasm of HUVEC, and also that decrease of ACE activity in the serum of septic adult respiratory distress syndrome (ARDS) patients might be due to reduced synthesis by vascular endothelial cells.

Angiotensin-converting enzyme and angiotensin II receptor subtype 2 genotypes in type 1 diabetes and severe hypoglycaemia requiring emergency treatment: a case cohort study

In type 1 diabetes, individual susceptibility to severe hypoglycaemia is likely to be influenced by genetic factors. We have previously reported an association of the deletion (D-) allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the A-allele of the angiotensin II receptor subtype 2 (AT2R) 1675 G>A polymorphism with risk of severe hypoglycaemia in such patients. The aim of this study was to test the hypothesis that these alleles are more frequent in patients suffering from the most severe episodes of hypoglycaemia requiring medical emergency treatment. The case cohort study consisted of 108 cases of type 1 diabetic patients with severe hypoglycaemia requiring medical emergency treatment during a 1-year period and 262 consecutive controls without such events. ACE I/D and AT2R 1675G>A genotype distributions were compared between cases and controls. The proportion of D-allele carriers was higher amongst cases than controls (83 vs. 73%; P=0.032). In contrast, AT2R genotype distribution was similar in cases and controls. In a multiple regression analysis, D-allele carriage remained a significant risk factor for being a case [odds ratio: 1.9 (1.0-3.6)] together with male sex, impaired symptomatic awareness of hypoglycaemia and presence of nephropathy. The D-allele of the ACE gene is associated with severe hypoglycaemia requiring emergency treatment in type 1 diabetic patients with preserved spontaneous ACE activity. This supports the association between high ACE activity and occurrence of severe hypoglycaemia.

ACE I/D polymorphism associated with abnormal atrial and atrioventricular conduction in lone atrial fibrillation and structural heart disease: Implications for electrical remodeling

The angiotensin-converting enzyme (ACE) gene contains a common polymorphism based on the insertion (I) or deletion (D) of a 287-bp intronic DNA fragment. The D allele is associated with higher ACE activity and thus higher angiotensin II levels. Angiotensin II stimulates cardiac fibrosis and conduction heterogeneity. The purpose of this study was to determine whether the ACE I/D polymorphism modulates cardiac electrophysiology. Three different cohorts of patients were studied: 69 patients with paroxysmal lone atrial fibrillation (AF), 151 patients with structural heart disease and no history of AF, and 161 healthy subjects without cardiovascular disease or AF. Patients taking drugs that affect cardiac conduction were excluded from the study. ECG parameters during sinus rhythm were compared among the ACE I/D genotypes. The ACE I/D polymorphism was associated with the PR interval and heart block in the lone AF cohort. In multivariable linear regression models, the D allele was associated with longer PR interval in the lone AF and heart disease cohorts (12.0-ms and 7.1-ms increase per D allele, respectively). P-wave duration showed a similar trend, with increase in PR interval across ACE I/D genotypes in the lone AF and heart disease cohorts. The ACE D allele is associated with electrical remodeling in patients with lone AF and in those with heart disease, but not in control subjects. ACE activity may play a role in cardiac remodeling after the development of AF and heart disease.

Differential ACE expression among tissues in allele-specific Wistar rat lines

In humans, the insertion/deletion polymorphism in the angiotensin converting enzyme (ACE) gene accounts for half of the variance in plasma ACE activity. The deletion allele is associated with high plasma ACE activity, cardiovascular disease, and renal disease. In rat, a similar association is found between the B and L alleles of a microsatellite marker in the ACE gene. We identified the B/L variation in the Wistar outbred rat and bred two lines homozygous for the two alleles (WU-B and WU-L). ACE activity was measured in serum, heart, kidney, and aorta homogenates. Immunohistochemistry and ACE mRNA expression were performed in heart, kidney, and aortic tissue. Aortic rings were collected and stimulated with AngI, AngII, and AngI with Lisinopril to measure ACE functional activity by vasoconstrictor response. Serum, heart, and kidney ACE activity and kidney mRNA expression were two-fold higher in WU-B. Kidney staining showed a clear difference in tubular ACE expression, with more staining in WU-B. While in aorta ACE activity and mRNA expression was twofold higher in WU-L, functional conversion of AngI was higher in WU-B, indicating either a functional difference in AngI to AngII conversion between the two alleles due to different splicing or the presence of other factors involved in the conversion that are differentially expressed as the result of differences in the ACE alleles. The newly developed WU-B and WU-L lines show tissue-specific differences in ACE expression and activity. This provides an experimental tool to study the pathophysiologic consequences of differences in ACE alleles in renal and cardiovascular disease.

Stunting growth: association of the blood pressure levels and ACE activity in early childhood

Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II and inactive bradykinin. Several studies carried out in our laboratory have consistently identified three isoforms of ACE, at 65, 90 and 190 kDa, with the 90-kDa isoform being a possible genetic marker of hypertension. Based on these observations and the fact that nutritional stunting can be associated with hypertension, we have investigated the expression and activity of ACE in stunted children and its association with blood pressure (BP) levels and nutritional state. Sixty children aged 2-7 years were selected for this study. A urine sample was collected from each child. Angiotensin converting enzyme activity was evaluated using two different substrates, and ACE expression was detected by Western blotting. Our results show that nutritional stunting is associated with high ACE activity in childhood and that adjustment by gender does not modify the strength of this association. A greater percentage of stunted children had increased BP levels, and this clinical parameter was inversely correlated with anthropometric indicators. A greater urinary protein expression of the three ACE isoforms was observed in the group of children with growth stunting. Our findings suggest that the reported high risk of hypertension in stunted adolescents and adults are, at least partly, associated with abnormalities in the renin-angiotensin system.