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

Bánhegyi, Viktor; Enyedi, Ágnes; Fülöp, Gábor; Oláh, Attila; Siket, Ivetta Mányiné; Váradi, Csaba; Bottyán, Klaudia; Lódi, Mária; Csongrádi, Alexandra; Umar, Azeem J.; Fagyas, Miklós; Czuriga, Dániel; Édes, István; Pólos, Miklós; Merkely, Béla; Csanádi, Zoltán; Papp, Zoltán; Szabó, Gábor; Radovits, Tamás; Takács, István; Tóth, Attila

doi:10.3390/cells10071708

Cited by 17 publications

(23 citation statements)

References 37 publications

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“…Perhaps the normal age-related protective response (posited above) may become dysfunctional in AD, for instance in the presence of Aβ peptides. Alternatively, disease-associated post-translational modification, altered secretion, or changes in the concentrations of potential endogenous inhibitors of ACE-1, may account for disparities between ACE-1 protein and activity in AD ( 38 ). We did not observe disease-associated changes to ACE-2 activity in this study compared to our previous study ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease

MacLachlan

Kehoe

Miners

2022

The Journals of Gerontology: Series A

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An imbalance in the renin-angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer’s disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n=121) (19-95y age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, UK, and AD and age-matched controls (n=60) from the South West Dementia Brain Bank, University of Bristol, UK, stratified according to Braak tangle stage (BS): 0-II, III-IV (intermediate disease) and V-VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and angiotensin-II (Ang-II) protein level was measured by ELISA. In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal ageing. ACE-1 enzyme activity was elevated at an early/intermediate stage i.e. BS III-IV compared to BS 0-II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease

MacLachlan

Kehoe

Miners

2022

The Journals of Gerontology: Series A

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“…The collection of human samples was approved by the Ethics Committee of the University of Debrecen (Hungary) as described in detail previously [ 27 ]. All corresponding procedures were carried out in accordance with institutional guidelines and the Code of Ethics of the World Medical Association (Declaration of Helsinki).…”

Section: Methodsmentioning

confidence: 99%

Urinary ACE Phenotyping as a Research and Diagnostic Tool: Identification of Sex-Dependent ACE Immunoreactivity

et al. 2023

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Background: Angiotensin-converting enzyme (ACE) is highly expressed in renal proximal tubules, but ACE activity/levels in the urine are at least 100-fold lower than in the blood. Decreased proximal tubular ACE has been associated with renal tubular damage in both animal models and clinical studies. Because ACE is shed into urine primarily from proximal tubule epithelial cells, its urinary ACE measurement may be useful as an index of tubular damage. Objective and Methodology: We applied our novel approach—ACE phenotyping—to characterize urinary ACE in volunteer subjects. ACE phenotyping includes (1) determination of ACE activity using two substrates (ZPHL and HHL); (2) calculation of the ratio of hydrolysis of the two substrates (ZPHL/HHL ratio); (3) quantification of ACE immunoreactive protein levels; and (4) fine mapping of local ACE conformation with mAbs to ACE. Principal findings: In normal volunteers, urinary ACE activity was 140-fold less than in corresponding plasma/serum samples and did not differ between males and females. However, urinary ACE immunoreactivity (normalized binding of 25 mAbs to different epitopes) was strongly sex-dependent for the several mAbs tested, an observation likely explained by differences in tissue ACE glycosylation/sialylation between males and females. Urinary ACE phenotyping also allowed the identification of ACE outliers. In addition, daily variability of urinary ACE has potential utility as a feedback marker for dieting individuals pursuing weight loss. Conclusions/Significance: Urinary ACE phenotyping is a promising new approach with potential clinical significance to advance precision medicine screening techniques.

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“…However, some studies failed to discern any relationship between the ACE gene polymorphism and CAD in patients with diabetes [ 35 , 36 ]. A possible mechanism suggests that the ACE DD genotype is involved in increasing the vasoconstrictor angiotensin II as well as the degradation of the vasodilator bradykinin, which increases resistance to insulin [ 37 ]. Our results are consistent with data obtained from different studies [ 38 , 39 , 40 ]; we found that the ACE (rs4646994) D allele increases the risk of CAD in T2DM patients.…”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable that a gene–environment interaction may play a significant role in the predisposition to CAD [ 35 , 36 ]. The insertion/deletion (I/D) (rs4646994) polymorphism in intron 16 of the ACE gene is considered an important genetic determinant of CAD and hypertension [ 37 , 42 ]. There is controversy related to the role of the ACE D/I polymorphism in the risk of CAD and myocardial infarction (MI) [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical Utility of Amplification Refractory Mutation System-Based PCR and Mutation-Specific PCR for Precise and Rapid Genotyping of Angiotensin-Converting Enzyme 1 (ACE1-rs4646996 D>I) and Angiotensin-Converting Enzyme 2 (ACE2-rs4240157T>C) Gene Variations in Coronary Artery Disease and Their Strong Association with Its Disease Susceptibility and Progression

et al. 2022

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Background: Experimental clinical and research studies demonstrated that the renin–angiotensin system (RAS) affects the pathogenesis of atherosclerosis and the prognosis of coronary heart disease (CHD). The results show that ACE2 (angiotensin I-converting enzyme 2) might act as a protective protein for cardiovascular diseases; however, only a few studies in human populations have been carried out. The aim of this study was to develop, optimize, and validate a direct T-ARMS-based PCR assay for the precise and rapid genotyping of ACE1-rs4646996 D>I and ACE2-rs4240157T>C and study their association with coronary artery disease susceptibility and progression. Methodology: This study included 149 consecutive coronary artery disease patients and 150 healthy controls. We utilized T-ARMS for the precise and rapid genotyping of ACE2-rs4240157; rs4646994. Results: Our results indicated that the ACE1-rs4646996 D>I genotypes observed between CAD cases and controls were statistically significant (p < 0.008) and, similarly, the ACE2-rs4240157T>C genotypes observed were significant (p < 0.0001). Moreover, the frequency of the D allele (ACE1-D>I) and C allele (ACE2-rs4240157T>C) was found to be higher among CAD patients than the HC. Our results indicated that in the codominant model, the ACE2-ID genotype was strongly associated with increased CAD susceptibility in a codominant model with an OR of 2.37, (95%) CI = (1.023–5.504), and p < 0.04. Similarly, the ACE2-DD genotype was strongly associated with an increased CAD susceptibility with an OR of 3.48, (95%) CI = (1.49 to 8.117), and p < 0.003. Similarly, in allelic comparison, the D allele was strongly associated with CAD susceptibility with an OR of 1.59, (95%) CI = (1.12–2.24), and p < 0.003. Our results revealed that there was a significant correlation between ACE2-I/D genotypes and hypertension, T2D, and obesity (p < 0.05). The results of ACE2 rs4240157 genotyping indicated a strong association in the codominant model with an increased CAD susceptibility with an OR of 3.62, (95%) CI = (2.027 to 6.481), and p < 0.0001. Similarly, in a dominant inheritance model, a strong association is observed between the ACE2 rs4240157 (CT+CC) genotype with an OR of 6.34, (95%) CI = (3.741 to 10.749), and p < 0.0001. In allelic comparison, the T allele was strongly associated with CAD susceptibility with an OR of 5.56, (95% CI = (3.56 to 7.17), and p < 0.0001. Similarly, our results revealed that there was a significant association of the ACE2-rs4240157T>C genotypes with Triglycerides (mg/dL), HDL-C (mg/dL), total Cholesterol (mg/dL), and C-reactive protein (mg/L) in CAD. Conclusion: It was indicated that the ARMS technique and MS-PCR assay proved to be fast, accurate, and reliable for ACE2-rs4240157T>C and ACE1-rs4646996 D>I, respectively, and can be used as a potential molecular tool in the diagnosis of genetic diseases in undeveloped and developing countries—where there might be a shortage of medical resources and supplies. ACE1-I>D genotypes were strongly associated with T2D, hypertension, and obesity (p < 0.002). Besides the ACE2-rs4240157 CT heterozygosity genotype, the T allele was strongly associated with CAD susceptibility. Future longitudinal studies in different ethnic populations with larger sample sizes are recommended to validate these findings

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

Cited by 17 publications

References 37 publications

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease

Urinary ACE Phenotyping as a Research and Diagnostic Tool: Identification of Sex-Dependent ACE Immunoreactivity

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