The testicular transcript of the angiotensin I‐converting enzyme encodes for the ancestral, non‐duplicated form of the enzyme

Lattion, Anne-Laure; Soubrier, Florent; Allegrini, J; Hübert, Christine; Corvol, Pierre; Alhenc-Gélas, François

doi:10.1016/0014-5793(89)80897-x

Cited by 156 publications

(81 citation statements)

References 27 publications

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“…15,[22][23][24][25]35,36 ACE inhibitors bind to both active sites, but depending on their structure, they may differ in their affinities, primarily because of differences in dissociation rates from the two active sites. 32,37,38 We discovered in human ileal fluid collected after surgery a naturally occurring, short form of ACE having only the N-domain active site; the molecular mass of this deglycosylated ACE is 68 kD.…”

Section: Discussionmentioning

confidence: 99%

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

et al. 1998

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Abstract-We used the isolated N-and C-domains of the angiotensin I-converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1-7 derivative of angiotensin (Ang) II and inhibition by 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE). Ang-(1-7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC 50 of C-ACE with 100 mol/L Ang I substrate was 1.2 mol/L and the K i was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38-to 47-times lower concentration than by N-ACE; IC 50 values with C-ACE were 0.5 and 0.04 mol/L. Furthermore, we investigated how Ang-(1-7) acts via bradykinin and the involvement of its B 2 receptor. Ang-(1-7) was ineffective directly on the human bradykinin B 2 receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1-7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 mol/L), acting on the B 2 receptor when the cells were cotransfected with cDNAs of both B 2 receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1-7) can potentiate the actions of a ligand of the B 2 receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1-7).(Hypertension. 1998;31:912-917.)

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Section: Discussionmentioning

confidence: 99%

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

et al. 1998

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“…This protein, termed testis ACE, is the result of a tissuespecific promoter located within intron 12 of the ACE gene (21). Testis ACE corresponds to the COOH-terminal half of somatic ACE and contains only the COOHterminal catalytic domain (15,29,30). As described below, studies in knockout mice have proven that testis ACE plays a critical role in male fertility.…”

Section: Ace1: Mice Null For Acementioning

confidence: 99%

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Cole

Xiao

Adams

et al. 2003

American Journal of Physiology-Renal Physiology

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. New approaches to genetic manipulation of mice: tissue-specific expression of ACE. Am J Physiol Renal Physiol 284: F599-F607, 2003; 10.1152/ajprenal.00308. 2002The renin-angiotensin system (RAS) plays a central role in body physiology, controlling blood pressure and blood electrolyte composition. ACE.1 (null) mice are null for all expression of angiotensin-converting enzyme (ACE). These mice have low blood pressure, the inability to concentrate urine, and a maldevelopment of the kidney. In contrast, ACE.2 (tissue null) mice produce one-third normal plasma ACE but no tissue ACE. They also have low blood pressure and cannot concentrate urine, but they have normal indices of renal function. These mice, while very informative, show that the null approach to creating knockout mice has intrinsic limitations given the many different physiological systems that no longer operate in an animal without a functioning RAS. To investigate the fine control of body physiology by the RAS, we developed a novel promoter swapping approach to generate a more selective tissue knockout of ACE expression. We used this to create ACE.3 (liver ACE) mice that selectively express ACE in the liver but lack all ACE within the vasculature. Evaluation of these mice shows that endothelial expression of ACE is not required for blood pressure control or normal renal function. Targeted homologous recombination has the power to create new strains of mice expressing the RAS in selected subsets of tissues. Not only will these new genetic models be useful for studying blood pressure regulation but also they show great promise for the investigation of the function of the RAS in complicated disease models.angiotensin-converting enzyme; blood pressure; angiotensin II; liver; renin-angiotensin system ROUGHLY ONE-HALF OF ALL AMERICANS die from cardiovascular disease. Put differently, more Americans die of cardiovascular disease than the next seven leading causes of death combined (1). To understand cardiovascular disease, one must understand how the body regulates blood pressure, a complex process governed by many different components, including multiple vasoconstrictors and vasodilators. Among these is the renin-angiotensin system (RAS), which produces the vasoconstrictor angiotensin II. The basic physiology by which angiotensinogen is degraded to angiotensin II has been known for many years, with the importance of this system underscored by the enormous clinical utility of pharmaceuticals that interrupt angiotensin II formation or action. So with all that is known about the RAS, what could conceivably be new? In fact, the use of targeted homologous recombination in mouse embryonic stem (ES) cells has produced a startling series of insights into the operation and functional importance of the RAS. This progress has been so rapid and dramatic as to implicate the RAS as easily the most important regulator of cardiovascular function as measured through blood pressure control.The use of homologous recombination to modify genes relies on the properties of cul...

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“…6,7 The germinal isoform (90 -110 kDa), which is restricted to the testicle, is identical to the C-domain of somatic ACE. 8 ACE1 is present in most tissues in the form of a membrane-bound ectoenzyme; however, soluble forms of the enzyme are present in the lymph, blood plasma, 9 and urine. 10 Early works primarily focused on systemic RAS; however, the discovery of all of the components of the RAS in tissues that can function locally has given rise to the notion that local RAS may play a significant role in the local control of circulation.…”

mentioning

confidence: 99%

Tissue-Specific Upregulation of Angiotensin-Converting Enzyme 1 in Spontaneously Hypertensive Rats Through Histone Code Modifications

et al. 2012

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Abstract-The renin-angiotensin system has been implicated in the development of hypertension and damages several organs. The expressions of the components of a local renin-angiotensin system (RAS) in the hypertensive rats differ from those of the normotensive rats. We hypothesized that local tissue-specific upregulation of angiotensin-converting enzyme 1 (ACE1) in hypertension is caused by epigenetic changes. Adrenal gland, aorta, heart, kidney, liver, and lung tissues were excised from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Ace1 mRNA and protein expressions were measured by real-time PCR and Western blot, respectively. Promoter methylation was revealed by bisulfite sequencing. Histone modifications, such as histone 3 acetylation (H3Ac), fourth lysine trimethylation (H3K4me3), and ninth lysine dimethylation (H3K9me2), were quantified by chromatin immunoprecipitation (ChIP), followed by real-time PCR. The expressions and associations of chromatin remodeling genes were analyzed by real-time PCR and ChIP, respectively. Local tissues from SHRs showed higher expressions of Ace1 mRNA and protein than those from the WKY rats. Ace1 promoter was mostly unmethylated in all of the tissues from both strains. The Ace1 promoter regions of SHR tissues were more enriched with H3Ac and H3K4me3, except in the lungs.

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The testicular transcript of the angiotensin I‐converting enzyme encodes for the ancestral, non‐duplicated form of the enzyme

Cited by 156 publications

References 27 publications

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme

New approaches to genetic manipulation of mice: tissue-specific expression of ACE

Tissue-Specific Upregulation of Angiotensin-Converting Enzyme 1 in Spontaneously Hypertensive Rats Through Histone Code Modifications

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