Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human epidemiological studies have shown that low birth weight is associated with hypertension in adulthood. Rodent models of intrauterine growth retardation (IUGR) support these findings because offspring from undernourished dams develop hypertension. Angiotensin-converting enzyme 2 (ACE2) is a newly described renin-angiotensin system (RAS) component that competes with ACE for angiotensin peptide hydrolysis and therefore may modulate blood pressure. However, ACE2 potential participation in hypertension programming remains unknown, although RAS alterations were reported in IUGR models. Hence, we first investigated the tissue distribution of ACE2 and ACE in the rat and then whether hypertension programming differentially affects both enzymes. Using multiplex RT-PCR and in situ hybridization, we show that ACE2 mRNA is widely expressed and coregionalized with ACE. Moreover, tissues involved in blood pressure homeostasis (lung, heart, and kidney) express high levels of both enzymes. Enzymatic assays reveal that ACE2 and ACE are coactive in these tissues. Adult (4-month-old) offspring from 70% food-restricted dams throughout gestation (FR30 rats) present mild hypertension, impaired renal morphology, as well as elevated plasma angiotensin II and aldosterone, suggesting alterations of the systemic RAS. In FR30 rats, we show that ACE2 and ACE activities are increased only in the lung, whereas their mRNA expression is not significantly altered, showing that the enzymes display tissue-specific sensitivity to programming. Our results indicate that ACE2 and ACE are coexpressed in numerous rat tissues and that their increased activity in the lung of FR30 rats may participate in hypertension programming.
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PMID:Angiotensin-converting enzyme 2 (ACE2) and ACE activities display tissue-specific sensitivity to undernutrition-programmed hypertension in the adult rat. 1620 74

Estrogen's suggested cardio-protective effects have come into question following the results of recent clinical trials. Two major components of the renin-angiotensin system (RAS) that are modulated by estrogen are angiotensin converting enzyme, and the angiotensin II type 1 receptor. Further research has revealed several new components of the RAS, including angiotensin converting enzyme 2, its peptide product angiotensin 1-7 (Ang 1-7), and that peptide's receptor, Mas. These components appear to oppose the classical effects of the RAS, and may act to buffer the RAS in vivo. Recent work has shown that during pregnancy, when estradiol levels are elevated, renal and urinary Ang 1-7 are greatly increased. This study examined the effects of estradiol on the efficacy of Ang 1-7 in the rat aorta. Female Sprague-Dawley rats were ovariectomized and a subgroup was chronically treated with subcutaneous pellets of estradiol for 3 weeks. Thoracic aortas were harvested for assessment of in vitro vascular reactivity to Ang 1-7. The results demonstrated that increased estradiol exposure attenuated the relaxation response to Ang 1-7 in a dose-dependent manner. These findings are in contrast to recent work showing potentiated responses to Ang 1-7 in mesenteric arteries from estrogen-manipulated rats, and may suggest a regional specificity in estradiol-mediated changes in the RAS.
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PMID:Alterations in aortic vascular reactivity to angiotensin 1-7 in 17-beta-estradiol-treated female SD rats. 1621 74

Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE, which is not blocked by ACE inhibitors. High amounts of ACE2 are present in the proximal tubule, and ACE2 catalyzes generation of angiotensin 1-7 (Ang-(1-7)) by this segment. Ang-(1-7) binds to a receptor distinct from the AT1 or AT2 Ang II receptor, identified as the mas receptor. We studied the effects of Ang-(1-7) on Ang II-mediated cell signaling pathways in proximal tubule. In primary cultures of rat proximal tubular cells, activation of mitogen-activated protein kinases (MAPK) was detected by immunoblotting, in the presence or absence of agonists/antagonists. Transforming growth factor-beta1 (TGF-beta1) was measured by enzyme-linked immunosorbent assay. Ang II (5 min, 10(-7) M) stimulated phosphorylation of the three MAPK (p38, extracellular signal-related kinase (ERK 1/2), and c-Jun N-terminal kinase (JNK)). While incubation of proximal tubular cells with Ang-(1-7) alone did not significantly affect MAPK phosphorylation, Ang-(1-7) (10(-7) M) completely inhibited Ang II-stimulated phosphorylation of p38, ERK 1/2, and JNK. This inhibitory effect was reversed by the Ang-(1-7) receptor antagonist, D-Ala7-Ang-(1-7). Ang II significantly increased production of TGF-beta1 in proximal tubular cells, an effect that was partly inhibited by Ang-(1-7). Ang-(1-7) had no significant effect on cyclic 3',5'-adenosine monophosphate production in these cells. In summary, Ang-(1-7) inhibits Ang II-stimulated MAPK phosphorylation in proximal tubular cells. Generation of Ang-(1-7) by proximal tubular ACE2 could thereby serve a protective role by counteracting the effects of locally generated Ang II.
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PMID:Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. 1667 6

The abnormal development of the intrarenal renin-angiotensin system (RAS) is thought contribute to adult-onset hypertension in the spontaneously hypertensive rat (SHR). Angiotensin-converting enzyme 2 (ACE2) is a novel enzyme with complementary actions to that of ACE. Recent studies have shown that ACE2 expression is reduced in the adult SHR. However, its regulation in pre-hypertensive animals is unknown. In this study, we examine the developmental expression of ACE2 in the rodent kidney and its temporal expression, as it relates to the development of hypertension in the SHR model. Kidneys from SHR and normotensive Wistar Kyoto (WKY) rats (n=8-12/group) at birth, 6 weeks of age, and adulthood (80 days) were examined. Gene expression and activity of ACE2 were determined by real-time reverse transcription-polymerase chain reaction and quenched fluorescence assays, respectively. Renal expression was localized by in situ hybridization and immunohistochemistry. The expression and ACE2 activity are significantly increased in the SHR kidney at birth. With the onset of hypertension, the tubular expression of ACE2 falls in SHR compared to WKY and remains reduced in the adult SHR kidney. Glomerular expression is paradoxically increased in the SHR glomerulus. The overall developmental pattern of ACE2 expression in the SHR kidney is also modified, with declining expression over the course of renal development. The developmental pattern of ACE2 expression in the SHR kidney is altered before the onset of hypertension, consistent with the key role of the RAS in the pathogenesis of adult-onset hypertension. Further research is required to distinguish the contribution of these changes to the development and progression of hypertension in this model.
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PMID:Developmental expression of ACE2 in the SHR kidney: a role in hypertension? 1681 Feb 85

Angiotensin-converting enzyme 2 (ACE2), a newly identified member in the renin-angiotensin system (RAS), acts as a negative regulator of ACE. It is mainly expressed in cardiac blood vessels and the tubular epithelia of kidneys and abnormal expression has been implicated in diabetes, hypertension and heart failure. The mechanism and physiological function of this zinc metallopeptidase in mammals are not yet fully understood. Non-mammalian vertebrate models offer attractive and simple alternatives that could facilitate the exploration of ACE2 function. In this paper we report the in silico analysis of Ace2 genes from the Gallus (chicken), Xenopus (frog), Fugu and Tetraodon (pufferfish) genome assembly databases, and from the Danio (zebrafish) cDNA library. Exon ambiguities of Danio and Xenopus Ace2s were resolved by RT-PCR and 3'RACE. Analyses of the exon-intron structures, alignment, phylogeny and hydrophilicity plots, together with the conserved synteny among these vertebrates, support the orthologous relationship between mammalian and non-mammalian ACE2s. The putative promoters of Ace2 from human, Tetraodon and Xenopus tropicalis drove the expression of enhanced green fluorescent protein (EGFP) specifically in the heart tissue of transgenic Xenopus thus making it a suitable model for future functional genomic studies. Additionally, the search for conserved cis-elements resulted in the discovery of WGATAR motifs in all the putative Ace2 promoters from 7 different animals, suggesting a possible role of GATA family transcriptional factors in regulating the expression of Ace2.
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PMID:ACE2 orthologues in non-mammalian vertebrates (Danio, Gallus, Fugu, Tetraodon and Xenopus). 1678 Oct 89

ACE-related carboxypeptidase (ACE2) may counterbalance the angiotensin (ANG) II-promoting effects of ACE in tissues where both enzymes are found. Alterations in renal ACE and ACE2 expression have been described in experimental models of diabetes, but ACE2 activity was not assessed in previous studies. We developed a microplate-based fluorometric method for the concurrent determination of ACE and ACE2 activity in tissue samples. Enzymatic activity (relative fluorescence unit [RFU] . microg protein(-1) . h(-1)) was examined in ACE and ACE2 knockout mice and in two rodent models of diabetes, the db/db and streptozotocin (STZ)-induced diabetic mice. In kidney cortex, preparations consisting mainly of proximal tubules and cortical collecting tubules, ACE2 activity had a strong positive correlation with ACE2 protein expression (90-kDa band) in both knockout models and their respective wild-type littermates (r = 0.94, P < 0.01). ACE activity, likewise, had a strong positive correlation with renal cortex ACE protein expression (170-kDa band) (r = 0.838, P < 0.005). In renal cortex, ACE2 activity was increased in both models of diabetes (46.7 +/- 4.4 vs. 22.0 +/- 4.7 in db/db and db/m, respectively, P < 0.01, and 22.1 +/- 2.8 vs. 13.1 +/- 1.5 in STZ-induced diabetic versus untreated mice, respectively, P < 0.05). ACE2 mRNA levels in renal cortex from db/db and STZ-induced diabetic mice, by contrast, were not significantly different from their respective controls. In cardiac tissue, ACE2 activity was lower than in renal cortex, and there were no significant differences between diabetic and control mice (db/db 2.03 +/- 0.23 vs. db/m 1.85 +/- 0.10; STZ-induced diabetic 0.42 +/- 0.04 vs. untreated 0.52 +/- 0.07 mice). ACE2 activity in renal cortex correlated positively with ACE2 protein in db/db and db/m mice (r = 0.666, P < 0.005) as well as in STZ-induced diabetic and control mice (r = 0.621, P < 0.05) but not with ACE2 mRNA (r = -0.468 and r = -0.522, respectively). We conclude that in renal cortex from diabetic mice, ACE2 expression is increased at the posttranscriptional level. The availability of an assay for concurrent measurement of ACE and ACE2 activity should be helpful in the evaluation of kidney-specific alterations in the balance of these two carboxypeptidases, which are involved in the control of local ANG II formation and degradation.
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PMID:ACE and ACE2 activity in diabetic mice. 1680 85

The discovery of angiotensin-converting enzyme 2 (ACE-2) has revealed a far more complex enzymatic cascade that may influence the renin-angiotensin system within the kidney, specifically the expression of the functional products angiotensin II (Ang II) and Ang-(1-7). The regulation of this critical system involved in blood pressure control must now encompass the integral relationship of ACE and ACE-2 activities.
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PMID:ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1-7). 1671 Mar 53

Angiotensin-converting enzyme 2 (ACE2) expression has been shown to be altered in renal tubules from diabetic mice. This study examined the localization of ACE and ACE2 within the glomerulus of kidneys from control (db/m) and diabetic (db/db) mice and the effect of chronic pharmacologic ACE2 inhibition. ACE2 co-localized with glomerular epithelial cell (podocyte) markers, and its localization within the podocyte was confirmed by immunogold labeling. ACE, by contrast, was seen only in glomerular endothelial cells. By immunohistochemistry, in glomeruli from db/db mice, strong ACE staining was found more frequently than in control mice (db/db 64.6 +/- 6.3 versus db/m 17.8 +/- 3.4%; P < 0.005). By contrast, strong ACE2 staining in glomeruli from diabetic mice was less frequently seen than in controls (db/db 4.3 +/- 2.4 versus db/m 30.6 +/- 13.6%; P < 0.05). For investigation of the significance of reduced glomerular ACE2 expression, db/db mice were treated for 16 wk with a specific ACE2 inhibitor (MLN-4760) alone or combined with telmisartan, a specific angiotensin II type 1 receptor blocker. At the end of the study, glomerular staining for fibronectin, an extracellular matrix protein, was increased in both db/db and db/m mice that were treated with MLN-4760. Urinary albumin excretion (UAE) increased significantly in MLN-4760-treated as compared with vehicle-treated db/db mice (743 +/- 200 versus 247 +/- 53.9 microg albumin/mg creatinine, respectively; P < 0.05), and the concomitant administration of telmisartan completely prevented the increase in UAE associated with the ACE2 inhibitor (161 +/- 56; P < 0.05). It is concluded that ACE2 is localized in the podocyte and that in db/db mice glomerular expression of ACE2 is reduced whereas glomerular ACE expression is increased. The finding that chronic ACE2 inhibition increases UAE suggests that ACE2, likely by modulating the levels of glomerular angiotensin II via its degradation, may be a target for therapeutic interventions that aim to reduce albuminuria and glomerular injury.
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PMID:Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. 1702 Dec 63

There is an increasing body of evidence to suggest that the RAS (renin-angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-beta1, IL (interleukin)-1beta, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1-7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2-angiotensin-(1-7)-Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.
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PMID:Liver fibrosis: a balance of ACEs? 1760 May 27

The discovery of angiotensin-converting enzyme 2 (ACE2) in 2000 is an important event in the renin-angiotensin system (RAS) story. This enzyme, an homolog of ACE, hydrolyzes angiotensin (Ang) I to produce Ang-(1-9), which is subsequently converted into Ang-(1-7) by a neutral endopeptidase and ACE. ACE2 releases Ang-(1-7) more efficiently than its catalysis of Ang-(1-9) by cleavage of Pro(7)-Phe(8) bound in Ang II. Thus, the major biologically active product of ACE2 is Ang-(1-7), which is considered to be a beneficial peptide of the RAS cascade in the cardiovascular system. This enzyme has 42% identity with the catalytic domain of ACE, is present in most cardiovascular-relevant tissues, and is an ectoenzyme as ACE. Despite these similarities, ACE2 is distinct from ACE. Since it is a monocarboxypeptidase, it has only 1 catalytic site and is insensitive to ACE inhibitors. As a result, ACE2 is a central enzyme in balancing vasoconstrictor and proliferative actions of Ang II with vasodilatory and antiproliferative effects of Ang-(1-7). In this review, we will summarize the role of ACE2 in the cardiovascular system and discuss the importance of ACE2-Ang-(1-7) axis in the control of normal cardiovascular physiology and ACE2 as a potential target in the development of novel therapeutic agents for cardiovascular diseases.
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PMID:ACE2: a new target for cardiovascular disease therapeutics. 1770 27


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