Elevated Angiotensin-converting Enzyme Activity Research Articles

Exposure to low dose of Bisphenol A (BPA) intensifies kidney oxidative stress, inflammatory factors expression and modulates Angiotensin II signaling under hypertensive milieu.

Humans are constantly exposed to low concentrations of ubiquitous environmental pollutant, Bisphenol A (BPA). Due to the prevalence of hypertension (one of the major risk factors of cardiovascular disease [CVD]) in the population, it is necessary to explore the adverse effect of BPA under hypertension associated pathogenic milieu. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME) induced hypertensive Wistar rats to low dose BPA (50 μg/kg) for 30 days period. In tissue samples immunohistochemistry, real-time quantitative polymerase chain reaction and enzymatic assays were conducted. Moreover, studies on primary kidney cell culture were employed to explore the impact of low dose of BPA exposure at nanomolar level (20-80 nM range) on renal cells through various fluorescence assays. The observed results illustrate that BPA exposure potentiates/aggravates hypertension induced tissue abnormalities (renal fibrosis), oxidative stress (ROS generation), elevated angiotensin-converting enzyme activity, malfunction of the antioxidant and tricarboxylic acid cycle enzymes, tissue lipid abnormalities and inflammatory factor expression (both messenger RNA and protein level of TNF-α and IL-6). Further, in vitro exposure of nM levels of BPA to primary kidney cells modulates oxidative stress (both superoxide and total ROS), mitochondrial physiology (reduced mitochondrial transmembrane potential-∆ψm) and lipid peroxidation in a dose dependent manner. In addition, angiotensin II induced ROS generation was aggravated further by BPA during coexposure in kidney cells. Therefore, during risk assessment, a precise investigation on BPA exposure in hypertensive (CVD vulnerable) populations is highly suggested.

Relevance of oxidative stress biomarkers, hemoglobin A1c, troponin-I, and angiotensin-converting enzyme metabolism to blood pressure in acute myocardial infarction: a case-control study

ABSTRACTThe aim was to investigate this relationship by calculating 1) the correlation between peak troponin-C (peak-cTnI), levels of oxidative stress biomarkers, including lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CD)), and antioxidant enzyme activity (glutathione peroxidase (GPx)), and HbA1c and 2) the correlation between HbA1c and serum angiotensin-converting enzyme (ACE) activity, and its impact on the rate pressure product (RPP) in acute myocardial infarction (AMI). A case-control study was performed in 306 AMI patients having undergone coronary angiography and on 410 controls. GPx activity was reduced in association with increased MDA and CD in patients. Peak-cTnI was positively correlated with HbA1c, MDA, and CD levels. Serum ACE activity was negatively correlated with GPx. HbA1c was positively correlated with ACE activity and RPP. Linear regression analysis showed that peak-cTnI, ACE activity and HbA1c are significant predictors of AMI. Elevated HbA1c and peak-cTnI levels are associated with RPP elevation causing AMI. In conclusions, patients with elevated HbA1c, elevated ACE activity and cTnI are at increased risk of AMI with increasing RPP. Patients at risk of AMI can be identified at an early stage if the biomarkers HbA1c, ACE activity, and cTnI are measured and preventive measures are taken in a targeted manner.

Extreme elevation of serum angiotensin-converting enzyme (ACE) activity: always consider familial ACE hyperactivity

Measurement of serum angiotensin-converting enzyme (ACE) activity can be helpful in the diagnosis and disease monitoring of sarcoidosis. Elevated serum ACE activity is found in 60-70% of sarcoidosis patients. Usually, the ACE activity is mildly increased (<3-fold the upper limit of the reference range) in sarcoidosis patients. Extremely elevated ACE activity is suggestive of the benign condition known as 'familial hyperactivity of ACE'. Familial hyperactivity of ACE is a relatively rare condition and can be confirmed by genetic testing. Considering a genetic cause of strongly elevated serum ACE activity is important to prevent possible overdiagnostics. Here, we highlight the factors that may complicate the interpretation of serum ACE activity measurements, and we present two cases that illustrate the importance of interdisciplinary consultation when extremely elevated serum ACE activity is measured.

Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension.

Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH. Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH. We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity. We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH. Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.

Studies on Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Genotype Distributions in Turkish Preeclampsia Patients

Placental, immune and genetic factors are thought to play an important role in preeclampia (PE)'s pathophysiology. Angiotensin-Converting Enzyme (ACE) plays a vital role in the renin-angiotensin-system (RAS) which regulates blood pressure by converting angiotensin I into a powerfull vasoconstrictor angiotensin II. A deletion polymorphism (D allele) has been reported to be associated with elevated ACE activity. The aim of the this study was to investigate whether there is an association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism and PE. In this study, 120 preeclamptic and 116 normotensive Turkish pregnant women were genotyped for ACE I/D polymorphism and the distribution of genotype and allele frequencies of this polymorphism in preeclampsia and controls were evaluated. Codominant, dominant and recessive models were appplied in ACE gene I/D polymorphism. In the codominant model, DD genotype was found significantly more frequent in preeclampsia than controls (P = 0.016). Moreover, in dominant model (DD frequency versus DI+II frequency) there was a significant relation between DD genotype and preeclampsia (P = 0.006). D allele frequency was 64.6% in preeclampsia while it was 56.1% in controls (P = 0.062). In conclusion, there was significant difference in genotype distribution between preeclampsia and controls.

Chronic Inhibition of Central Angiotensin-Converting Enzyme Ameliorates Colchicine Induced Memory Impairment in Mice

Preclinical and clinical studies indicated involvement of the central renin-angiotensin system (RAS) in memory functions. However, the role of central angiotensin-converting enzyme (ACE) in memory function is still unclear. The present study investigated the involvement of central ACE in colchicine-induced memory impairment in the context of cholinergic function and oxidative stress. Memory impairment was induced by intracerebral colchicine administration in mice. The ACE inhibitor, perindopril (0.05 and 0.1 mg/kg/day), was administered orally for 14 days. Memory function was evaluated by the Morris water maze (MWM) test from the 14th day on after colchicine injection. Donepezil was used as a standard. Parameters of oxidative stress and cholinergic function, ACE activity in serum and the brain were estimated after the completion of behavioral studies. Colchicine caused memory impairment as revealed by no significant change in latency to reach a hidden platform in the MWM test. Furthermore, there was a significant increase in MDA, ROS, and nitrite levels with a reduction in GSH level and acetylcholinesterase (AChE) activity in the brain of colchicine-treated mice. Colchicine significantly increased brain ACE activity without affecting serum ACE. Donepezil prevented colchicine-induced memory impairment in mice. The antidementic effect of perindopril may be attributed to reduced oxidative stress and improvement in cholinergic function. Moreover, the elevated brain ACE activity was also inhibited by perindopril. The study showed that central ACE plays an important role in colchicine-induced memory deficit, corroborating a number of studies that show that treatment with ACE inhibitors could be neuroprotective.

Elevated ACE activity is not associated with asthma, COPD, and COPD co-morbidity

The angiotensin-converting enzyme (ACE) gene is a potential candidate gene for risk of asthma, COPD, and COPD co-morbidity. In 9034 Danish adults, we determined whether individuals homozygous or heterozygous for the ACE D allele are at greater risk of asthma, COPD, or COPD co-morbidity compared with ACE II homozygous individuals. In the general population, serum ACE activity increased with the number of D alleles (Kruskal-Wallis ANOVA: II vs. ID, p<0.001; ID vs. DD, p<0.001); however, this did not translate into altered risk of asthma or COPD. In the general population, the odds ratio (95% confidence interval) for asthma was 1.2 (0.9-1.4) for ID individuals and 1.2 (0.9-1.5) for DD individuals compared with II individuals. In the general population, the odds ratio for COPD was 0.9 (0.8-1.1) for ID individuals and 1.0 (0.8-1.2) for DD individuals compared with II individuals. Among patients with COPD, the odds ratio for ischemic heart disease was 1.1 (0.8-1.6) for ID individuals and 1.2 (0.8-1.7) for DD individuals compared with II individuals; corresponding odds ratios for hypertension were 1.1 (0.7-1.5) and 0.8 (0.5-1.2), and for low physical activity 0.9 (0.5-1.4) and 0.7 (0.4-1.2). The results were similar upon adjustment for sex, age, smoking status, body mass index, total cholesterol, and ACE inhibitor/angiotensin II type 1 receptor blocker use. These data suggest that lifelong genetically elevated ACE activity is not a major risk factor for asthma or COPD, or for ischemic heart disease, hypertension, and low physical activity in COPD patients.

Maternal Protein Restriction During Mouse Preimplantation Development Induces Vascular Dysfunction and Altered Renin-angiotensin-system Homeostasis in the Offspring.

Studies using rodent and domestic animal models have demonstrated that environmental conditions experienced during early development, either in vivo or in vitro, shape critical aspects of future growth, metabolism, physiology and cardiovascular health. In particular, we have previously demonstrated that maternal dietary protein restriction during discrete windows of gestation results in the development of hypertension in the adult mouse. Therefore, the aim of the current study was to investigate the potential mechanisms involved in the development of hypertension following maternal protein underntrtion. Following mating, virgin female MF-1 mice were randomly assigned to either normal protein diet for the entirety of gestation (NPD; 18% casein), isocaloric low protein diet for the entirety of gestation (LPD; 9% casein), or LPD exclusively during the preimplantation period (3.5 days), before returning to NPD for the remainder of gestation (Emb-LPD). At birth all litters were standardised to a mean of 6 (3 male and 3 females where possible). At 22 weeks of age, isolated mesenteric arteries from LPD and Emb-LPD males displayed attenuated responsiveness to the endothelial-independent vasodilator isoprenaline (P <0.04) and a trend towards an impaired responsiveness to the nitric oxide donor sodium nitroprusside (P <0.01) when compared to NPD arteries. At 28 weeks of age, female left kidneys were processed in glycol methacrylate, sectioned and, using stereological techniques, glomerular number was estimated using the physical fractionator principle. No difference was observed in mean female left kidney glomerular number between any of the treatment groups. LPD females displayed a significantly elevated serum angiotensin converting enzyme (ACE) activity (P =0.05), while Emb-LPD males and females had a significantly elevated lung ACE activity when compared to NPD offspring (P <0.05). These data demonstrate that maternal dietary protein restriction during discrete windows of gestation (preimplantation development, 3.5 days) programmes postnatal cardiovascular abnormalities through the development of vasodilator dysfunction in male resistance arteries, elevated ACE activity, but with minimal effects on kidney morphology.

Genetic Variation and Activity of the Renin-Angiotensin System and Severe Hypoglycemia in Type 1 Diabetes

Background The deletion-allele of the angiotensin-converting enzyme (ACE) gene and elevated ACE activity are associated with increased risk of severe hypoglycemia in type 1 diabetes. We explored whether genetic and phenotypic variations in other components of the renin-angiotensin system are similarly associated. Methods Episodes of severe hypoglycemia were recorded in 171 consecutive type 1 diabetic outpatients during a 1-year follow-up. Participants were characterized at baseline by gene polymorphisms in angiotensinogen, ACE, angiotensin-II receptor types 1 (AT1R) and 2 (AT2R), and by plasma angiotensinogen concentration and serum ACE activity. Results Three risk factors for severe hypoglycemia were identified: plasma angiotensinogen concentration in the upper quartile (relative rate [RR] vs. lower quartile 3.1, 95% confidence interval [CI,] 1.4-6.8), serum ACE activity in the upper quartile (RR vs. lower quartile 2.9, 95% CI, 1.3-6.2), and homo- or hemizygosity for the A-allele of the X chromosome-located AT2R 1675G/A polymorphism (RR vs. noncarriers 2.5, 95% CI, 1.4-5.0). The three risk factors contributed independently to prediction of severe hypoglycemia. A backward multiple regression analysis identified a high number of renin-angiotensin system-related risk factors and reduced ability to perceive hypoglycemic warning symptoms (impaired hypoglycemia awareness) as predictors of severe hypoglycemia. Conclusions High renin-angiotensin system activity and the A-allele of the AT2R 1675G/A polymorphism associate with high risk of severe hypoglycemia in type 1 diabetes. A potential preventive effect of renin-angiotensin system blocking drugs in patients with recurrent severe hypoglycemia merits further investigation.

ACE I/D-corrected Z-scores to identify normal and elevated ACE activity in sarcoidosis

The value of elevated serum angiotensin-converting enzyme (ACE) activity in the diagnosis and follow-up in sarcoidosis is a matter of ongoing debate. This may be at least related to the insertion (I)/deletion (D) polymorphism in the ACE gene (ACE I/D). ACE activity is influenced by the ACE I/D polymorphism. As a consequence, the use of one reference interval instead of three genotype-specific reference intervals for ACE activity may lead to a less precise interpretation of ACE activity. In order to assess whether determination of ACE activity indeed requires the ACE I/D genotype to be taken into account, we established ACE I/D-corrected reference intervals in healthy, Caucasian volunteers (n=200). In addition, ACE activities in ACE I/D genotyped patients suspected of or having sarcoidosis (n=129) were expressed as the Z-score related to ACE I/D-corrected reference intervals. Comparison of the Z-score with ACE activity in which ACE I/D is ignored rendered 8.5% misclassification of 'elevated' versus 'normal' ACE or vice versa. Our data demonstrate a convenient way to circumvent the use of three reference intervals by introducing a Z-score for ACE activity. It also illustrates the need to re-investigating the possible clinical value of serum ACE activity in sarcoidosis by considering ACE I/D.

Increased angiotensin-converting enzyme activity in a patient with severe ovarian hyperstimulation syndrome

Objective: To assess plasma angiotensin-converting enzyme (ACE) activity in a patient with severe ovarian hyperstimulation syndrome (OHSS). Design: Case report. Setting: Private, university-affiliated infertility practice. Patient(s): A 35-year-old woman with OHSS. Intervention(s): Clomiphene citrate induction of ovulation. Main Outcome Measure(s): Plasma ACE activity. Result(s): The patient had a brain stem infarction as a result of thrombosis caused by severe OHSS. Plasma ACE activity was significantly elevated and persisted long after resolution of the OHSS. Conclusion(s): Elevated ACE activity appears to have been associated with the development of OHSS in this patient. Further study of the ovarian renin-angiotensin system in the development of OHSS is warranted.

Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels.

The angiotensinogen T235 allele is associated with elevated plasma angiotensinogen levels whereas the angiotensin-converting enzyme (ACE) deletion (D) allele is associated with elevated ACE activity. It remains unclear, however, whether these genetically mediated elevations of angiotensinogen and ACE levels are functionally relevant Given that the renin-angiotensin system is subject to renin feedback regulation, we specifically investigated the associations between the angiotensinogen T235 allele and the ACE D allele with plasma renin and prorenin levels. Plasma levels of renin, prorenin, angiotensinogen, ACE and aldosterone, as well as angiotensinogen and ACE genotypes were determined in 228 men and 168 women (age 52-65 years), who had participated in a population survey in southern Germany. Subjects taking antihypertensive drugs or oestrogen replacement therapy were excluded. We corroborated previous findings demonstrating associations between the T235M polymorphism and plasma angiotensinogen levels (P < 0.05) and between the ACE I/D polymorphism and plasma ACE (P < 0.01). After adjustment for sex, age and blood pressure, the T235 allele of the angiotensinogen gene was also related to lower plasma prorenin (P < 0.03) and renin (P < 0.01) levels, but not to plasma ACE and aldosterone. By contrast, the ACE I/D polymorphism was not related to components of the system other than plasma ACE. The angiotensinogen T235 allele is associated with decreased renin levels. This finding may point to a mechanism that counteracts the genetic elevation of angiotensinogen plasma levels and, thus, the plasmatic angiotensin II-generating pathway in subjects carrying the angiotensinogen T235 allele. These results may help to explain discrepant findings regarding associations between this allele and cardiovascular disorders. Furthermore, the presumed feedback downregulation of renin levels supports the importance of angiotensinogen as a determinant of angiotensin II generation. Finally, no evidence was found suggesting that the ACE D allele affects components of the circulating renin-angiotensin system other than plasma ACE.

Relationship between serum angiotensin-converting enzyme activity and plasma plasminogen activator inhibitor activity in patients with recent myocardial infarction

An elevated level of angiotensin-converting enzyme (ACE) has been demonstrated to increase the risk of myocardial infarction. Plasminogen activator inhibitor (PAI) is the most important physiological inhibitor of tissue plasminogen activator in plasma. An elevated level of PAI has been reported to be associated with decreased fibrinolytic capacity and to constitute a marker of the risk for recurrent coronary thrombosis. We measured the serum ACE activity and plasma PAI activity in 34 patients with recent myocardial infarction, and evaluated the correlation between these two values by linear regression analysis. We also administered captopril (37.5 mg/day) to 17 of these patients and placebo to the other 17 patients at random, and compared the changes in PAI activity and ACE activity in these two groups over a 1-month period. There was a significant correlation between the serum ACE activity and the plasma PAI activity at baseline in the patients (r = 0.498, P < 0.01). The captopril-treated patients showed significantly reduced PAI activity (P < 0.01), and a concomitant decrease in ACE activity. These results suggest that elevated ACE activity is associated with impaired fibrinolysis and that treatment with an ACE inhibitor improves the fibrinolytic function in patients with recent myocardial infarction. The results also suggest that the renin-angiotensin system plays a role in the increased risk of ischemic cardiovascular events when it is activated, and in the reduction of risk of recurrent myocardial infarction by ACE inhibition.

Antenatal glucocorticoid therapy suppresses angiotensin-converting enzyme activity in rats with nitrofen-induced congenital diaphragmatic hernia

Background/Purpose: Neonates with congenital diaphragmatic hernia (CDH) have a high morbidity and mortality rate caused by pulmonary hypoplasia associated with pulmonary hypertension (PH). In experimental CDH, antenatal glucocorticoid therapy improves surfactant biochemical immaturity, enhances lung compliance, and induces morphological maturation in CDH rats. The effects of steroid therapy on preventing or treating PH in this condition have not been studied. Angiotensin converting enzyme (ACE), which is produced by the vascular endothelium, is implicated in the pathogenesis of pulmonary hypertension. The aim of this study was to evaluate the effect of antenatal glucocorticoid therapy on ACE activity and expression in CDH rat lungs. Methods: CDH was induced in fetal rats by the maternal administration of 100 mg nitrofen on day 9.5 of gestation (term, day 22). Dexamethasone (Dex) (0.25 mg/kg) was given by intraperitoneal injection on days 18.5 and 19.5 before delivery of the fetuses by cesarean section on day 21.5. Control animals received olive oil (OO) by gavage and normal saline (NS) as vehicle injection. ACE activity was measured spectrophotometrically in the lungs of rats from four treatment groups: CDH-NS, non-CDH-NS, CDH-Dex, and OO-NS controls. Total lung ACE activity (mU per lung) was significantly lower in CDH-NS ( P = .002) and CDH-Dex ( P = .004) rats compared with non-CDH-NS and OO-NS controls (9.1 ± 1.0 and 10.7 ± 1.3 v 16.2 ± 1.6 and 15.4 ± 1.7). When specific ACE activity (mU/mg protein) was derived by expressing ACE activity per milligram of lung protein, CDH-nS animals showed elevated specific ACE activity ( P = .05) compared compared with CDH-NS and Non-CDH-NS rats (4.0 ± 0.4 v 6.31 ± 1.1 and 5.83 ± 0.54). The specific ACE activity levels of CDH-Dex rats were equivalent to those seen in the lungs of OO-NS controls ( P = .24). Conclusion: Antenatal steroid therapy, by suppressing pulmonary ACE activity, may reduce the risk of pulmonary hypertension developing in human newborns with antenatally diagnosed CDH.

Relationship between serum angiotensin-converting enzyme activity and plasma plasminogen activator inhibitor activity in patients with recent myocardial infarction

Background An elevated level of angiotensin-converting enzyme (ACE) has been demonstrated to increase the risk of myocardial infarction. Plasminogen activator inhibitor (PAI) is the most important physiological inhibitor of tissue plasminogen activator in plasma. An elevated level of PAI has been reported to be associated with decreased fibrinolytic capacity and to constitute a marker of the risk for recurrent coronary thrombosis. Methods We measured the serum ACE activity and plasma PAI activity in 34 patients with recent myocardial infarction, and evaluated the correlation between these two values by linear regression analysis. We also administered captopril (37.5 mg/day) to 17 of these patients and placebo to the other 17 patients at random, and compared the changes in PAI activity and ACE activity in these two groups over a 1-month period. Results There was a significant correlation between the serum ACE activity and the plasma PAI activity at baseline in the patients (r = 0.498, P < 0.01). The captopril-treated patients showed significantly reduced PAI activity (P < 0.01), and a concomitant decrease in ACE activity. Conclusion These results suggest that elevated ACE activity is associated with impaired fibrinolysis and that treatment with an ACE inhibitor improves the fibrinolytic function in patients with recent myocardial infarction. The results also suggest that the renin-angiotensin system plays a role in the increased risk of ischemic cardiovascular events when it is activated, and in the reduction of risk of recurrent myocardial infarction by ACE inhibition.

Serum angiotensin-converting enzyme in multiple sclerosis.

To determine the extent and significance of serum angiotensin-converting enzyme (ACE) elevation in multiple sclerosis (MS) and the correlation between serum ACE activity and clinical and magnetic resonance imaging (MRI) indicators of disease activity. A retrospective cross-sectional study of 45 consecutive patients with clinically definite MS and a longitudinal study of 30 additional patients with clinically definite MS involved in a long-term study of neurologic function and MRI in MS. Comprehensive MS center of a tertiary care university hospital. A total of 75 patients with clinically definite MS and 31 healthy controls. Serum ACE activity was measured using a spectrophotometric assay and correlated with clinical indicators of disease activity and with total cerebral MS lesion volume measured by MRI. An elevated ACE activity was found in 17 (23%) of 75 patients with MS as compared with 2 (6%) of 31 healthy controls. Changes in serum ACE activity correlated with changes in total plaque volume on MRI. Serum ACE activity may be an indicator of disease activity in longitudinal analysis. Also, elevated ACE activity in a patient with otherwise typical MS need not raise suspicions of alternative diagnoses.

Suppression of angiotensin-converting enzyme expression and activity by shear stress.

Shear stress caused by the frictional forces of a fluid moving over a cell monolayer is an important regulator of gene expression. In this study, we investigated the effect of shear stress on angiotensin-converting enzyme (ACE) expression and promoter activity in vitro and on local vascular ACE activity in vivo. ACE activity measured in bovine pulmonary artery endothelial (BPAE) cells was reduced by 49.5% after exposure to a shear stress of 20 dyne/cm2 for 18 hours. Short-term shearing (2 hours) elevated ACE activity in BPAE cells, whereas long-term shearing produced a time-dependent reduction in ACE activity by 23.3%, 33.5%, and 48.9% at 8, 12, and 18 hours, respectively. Northern blot analysis revealed that shear stress (20 dyne/cm2 for 18 hours) significantly reduced ACE mRNA expression by 82%. To determine the mechanism of ACE activity and message reduction, the effect of shear on transcriptionally related events was determined in a rabbit aortic endothelial cell line (W3LUC) stably transfected with 1.3 kb of a rat ACE promoter/luciferase construct. Different shear stress magnitudes (5 to 20 dyne/cm2) caused suppression of luciferase activity by an average of 40.7%. ACE promoter activity was suppressed by 2 hours of shear stress (24.7%) and was further inhibited at time periods > 8 hours. In vivo elevations in shear stress were created by placing a stainless steel clip over a 12-mm region of the rat abdominal aorta. Restriction of vessel diameter increased blood flow velocity and caused reduction in vascular ACE activity by 40%. These studies suggest that elevations in the level of shear stress alter endothelial cell function by suppressing ACE gene and protein expression in vitro and in vivo.

Elevated serum angiotensin-converting enzyme activity in onchocerciasis.

Our objective was to measure serum angiotensin-converting enzyme (ACE) activity in patients with onchocerciasis. Serum ACE activity is commonly used in the diagnosis and follow-up of patients with sarcoidosis. However, serum ACE activity can also be elevated in a number of other granulomatous disorders. In onchocerciasis, a parasitic disease affecting millions of people in Africa and Central and South America, granulomatous tissue around adult worms has been identified, yet raised serum ACE activity has not been reported so far. We measured serum ACE activity in serum samples from 42 onchocerciasis patients and 39 endemic controls previously enrolled in two studies concerning the side effects after invermectin treatment in Sierra Leone, West Africa. The mean ACE activity in the patient group was 53.8 units/liter (S.D. 19.8) compared with 35.2 units/liter (S.D. 14.0) in the control group (p < 0.0001). Nine of 42 patients had elevated ACE activity (mean of the endemic controls +/- 2 S.D.) compared with 1 of 39 controls (p = 0.01). Sensitivity and specificity of elevated ACE in serum from onchocerciasis patients from Sierra Leone was 21 and 97%, respectively. ACE activity was not related to the microfilarial skin load or development of side effects after ivermectin treatment. Serum ACE activity can be elevated in onchocerciasis. Clinicians should be aware of this phenomenon when determining serum ACE activity in persons from endemic areas.

Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism.

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with differences in the plasma levels of ACE as well as with myocardial infarction, cardiomyopathy, left ventricular hypertrophy, and coronary artery disease. We determined the cardiac ACE activity and the ACE genotype in 71 subjects who died of noncardiac disorders. Cardiac ACE activity was significantly higher (P < .01) in subjects with the ACE DD genotype (12.7 +/- 1.9 mU/g wet wt) compared with subjects with the ID (8.7 +/- 0.8 mU/g) and the II (9.1 +/- 1.0 mU/g) genotypes. This difference was independent of sex, age, and the time required for tissue collection. Cardiac ACE activity is highest in subjects with the DD genotype. Elevated cardiac ACE activity in these subjects may result in increased cardiac angiotensin II levels, and this may be a mechanism underlying the reported association between the ACE deletion polymorphism and the increased risk for several cardiovascular disorders.

Angiotensin-converting enzyme inhibition reduces diabetes-induced vascular hypertrophy: morphometric studies.

Angiotensin-converting enzyme (ACE) activity and vascular mass are both increased in the mesenteric arteries of diabetic rats. As vascular hypertrophy may result from smooth muscle growth following increased formation of angiotensin II, we have examined the histological nature of the increase in mesenteric arterial mass and the role of elevated ACE activity in diabetic vascular hypertrophy by administration of an ACE inhibitor (perindopril). Cross-sectional area of the media was measured in perfusion-fixed mesenteric vessels of diabetic rats 3 weeks after streptozotocin injection. The media was significantly larger (63%) in mesenteric vessels of diabetic rats compared to age-matched control animals. Medial hypertrophy in these vessels was not associated with increased blood pressure or plasma renin activity but there was evidence for increased hemodynamic load due to hyperphagia and intestinal enlargement. Increased mesenteric ACE activity was involved in this process as there was significant inhibition of medial hypertrophy by perindopril. Other markers of cardiovascular hypertrophy such as left ventricular weight and aortic medial area were less affected, but increased in the diabetic group when corrected for significant body weight effects, consistent with a systemic influence of diabetes on cardiovascular mass. These data provide new insights into the mechanisms of vascular complications of diabetes and may have implications for the use of ACE inhibitors in preventing or arresting diabetes-associated vascular pathology.