Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) has been recognized for many years as critical pathway for blood pressure control and kidney functions. Although most of the well-known cardiovascular and renal effects of RAS are attributed to angiotensin-converting enzyme (ACE), much less is known about the function of ACE2. Experiments using genetically modified mice and inhibitor studies have shown that ACE2 counterbalances the functions of ACE and that the balance between these two proteases determines local and systemic levels of RAS peptides such as angiotensin II and angiotensin1-7. Ace2 mutant mice exhibit progressive impairment of heart contractility at advanced ages, a phenotype that can be reverted by loss of ACE, suggesting that these enzymes directly control heart function. Moreover, ACE2 is also found to be upregulated in failing hearts. In the kidney, ACE2 protein levels are significantly decreased in hypertensive rats, suggesting a negative regulatory role of ACE2 in blood pressure control. Moreover, ACE2 expression is downregulated in the kidneys of diabetic and pregnant rats and ACE2 mutant mice develop late onset glomerulonephritis resembling diabetic nephropathy. Importantly, ACE2 not only controls angiotensin II levels but functions as a protease on additional molecular targets that could contribute to the observed in vivo phenotypes of ACE2 mutant mice. Thus, ACE2 seems to be a molecule that has protective roles in heart and kidney. The development of drugs that could activate ACE2 function would allow extending our treatment options in diabetic nephropathy, heart failure, or hypertension.
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PMID:Angiotensin-converting enzyme II in the heart and the kidney. 1651 79

The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease. Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS). ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections. In the lung, ACE2 protects against acute lung injury in several animal models of ARDS. Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury. Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.
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PMID:Angiotensin-converting enzyme 2 in lung diseases. 1658 Dec 95

A novel assay was developed for evaluation of mouse angiotensin-converting enzyme (ACE) 2 and recombinant human ACE2 (rACE2) activity. Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (MS) with ProteinChip Array technology, ACE1 and ACE2 activity could be measured using natural peptide substrates. Plasma from C57BL/6 mice, kidney from wild-type and ACE2 knockout mice, and rACE2 were used for assay validation. Plasma or tissue extracts were incubated with angiotensin I (Ang I; 1296 m/z) or angiotensin II (Ang II; 1045 m/z). Reaction mixtures were spotted onto the ProteinChips WCX2 and peptides detected using surface-enhanced laser desorption/ionization time of flight MS. MS peaks for the substrates, Ang I and Ang II, and the generated peptides, Ang (1-7) and Ang (1-9), were monitored. The ACE2 inhibitor MLN 4760 (0.01 to 100 micromol/L) significantly inhibited rACE2 activity (IC50=3 nmol/L). Ang II was preferably cleaved by rACE2 (km=5 mumol/L), whereas Ang I was not a good substrate for rACE2. There was no detectable ACE2 activity in plasma. Assay specificity was validated in a model of ACE2 gene deletion. In kidney extract from ACE2-deficient mice, there was no generation of Ang (1-7) from Ang II. However, Ang (1-7) was produced when Ang I was used as a substrate. In conclusion, we developed a specific and sensitive assay for ACE2 activity, which used the natural endogenous peptide substrate Ang II. This approach allows for the rapid screening for ACE2, which has applications in drug testing, high-throughput enzymatic assays, and identification of novel substrates/inhibitors of the renin-angiotensin system.
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PMID:New mass spectrometric assay for angiotensin-converting enzyme 2 activity. 1658 21

Inhibition of the angiotensin-converting enzyme (ACE) protects against the progression of several cardiovascular diseases. Because of its dual role in regulating angiotensin II and bradykinin levels, the positive clinical effects of ACE inhibitors were thought to be the consequence of concomitant reductions in the production of angiotensin II and the degradation of bradykinin. Recent evidence suggests that some of the beneficial effects of ACE inhibitors on cardiovascular function and homeostasis can be attributed to novel mechanisms. These include the accumulation of the ACE substrate N-acetyl-seryl-aspartyl-lysyl-proline, which blocks collagen deposition in the injured heart, as well as the activation of an ACE signaling cascade that involves the activation of the kinase CK2 and the c-Jun N-terminal kinase in endothelial cells and leads to changes in gene expression. Moreover, at least one other ACE homologue (ACE2) is proposed to counteract the detrimental effects associated with the activation of the classical renin-angiotensin system. These data reveal hitherto unexpected levels of internal regulation of the renin-angiotensin system.
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PMID:Signaling by the angiotensin-converting enzyme. 1661 14

The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a backcross of the hypertensive (mRen2)27 transgenic rat with normotensive Lewis rats, provides a new model by which primary hypertension can be studied without the genetic variability found in the original strain. The purpose of this study was to characterize the Lew.Tg(mRen2) rats by dually investigating the effects of type 1 angiotensin II (ANG II) receptor (AT(1)) blockade and angiotensin-converting enzyme (ACE) activity inhibition on the ANG-(1-7)/ACE2 axis of the renin-angiotensin system in this new hypertensive model. The control of blood pressure elicited by 12-day administration of either lisinopril (mean difference change = 92 +/- 2, P < 0.05) or losartan (mean difference change = 69 +/- 2, P < 0.05) was associated with 54% and 33% increases in cardiac ACE2 mRNA and 54% and 43% increases in cardiac ACE mRNA, respectively. Lisinopril induced a 3.1-fold (P < 0.05) increase in renal cortical expression of ACE2, whereas losartan increased ACE2 mRNA 3.5-fold (P < 0.05). Both treatment regimens increased renal ACE mRNA 2.6-fold (P < 0.05). The two therapies augmented ACE2 protein activity, as well as increased cardiac and renal AT(1) receptor mRNAs. ACE inhibition reduced plasma ANG II levels (81%, P < 0.05) and increased plasma ANG-(1-7) (265%, P < 0.05), whereas losartan had no effect on the peptides. In contrast with what had been shown in normotensive rats, ACE inhibition decreased renal ANG II excretion and transiently decreased ANG-(1-7) excretion, whereas losartan treatment was associated with a consistent decrease in ANG-(1-7) urinary excretion rates. In response to the treatments, the expression of both renal cortical renin and angiotensinogen mRNAs was significantly augmented. The paradoxical effects of blockade of ANG II synthesis and activity on urinary excretion rates of the peptides and plasma angiotensins levels suggest that, in Lew.Tg(mRen2) congenic rats, a failure of compensatory ACE2 and ANG-(1-7)-dependent vasodepressor mechanisms may contribute both to the development and progression of hypertension driven by increased formation of endogenous ANG II.
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PMID:Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. 1676 48

The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II-dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II-induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure.
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PMID:Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. 1687 72

Despite the evidence that angiotensin-converting enzyme (ACE)2 is a component of the renin-angiotensin system (RAS), the influence of ACE2 on angiotensin metabolism within the kidney is not well known, particularly in experimental models other than rats or mice. Therefore, we investigated the metabolism of the angiotensins in isolated proximal tubules, urine, and serum from sheep. Radiolabeled [(125)I]ANG I was hydrolyzed primarily to ANG II and ANG-(1-7) by ACE and neprilysin, respectively, in sheep proximal tubules. The ACE2 product ANG-(1-9) from ANG I was not detected in the absence or presence of ACE and neprilysin inhibition. In contrast, the proximal tubules contained robust ACE2 activity that converted ANG II to ANG-(1-7). Immunoblots utilizing an NH(2) terminal-directed ACE2 antibody revealed a single 120-kDa band in proximal tubule membranes. ANG-(1-7) was not a stable product in the tubule preparation and was rapidly hydrolyzed to ANG-(1-5) and ANG-(1-4) by ACE and neprilysin, respectively. Comparison of activities in the proximal tubules with nonsaturating concentrations of substrate revealed equivalent activities for ACE (ANG I to ANG II: 248 +/- 17 fmol x mg(-1) x min(-1)) and ACE2 [ANG II to ANG-(1-7): 253 +/- 11 fmol x mg(-1) x min(-1)], but lower neprilysin activity [ANG II to ANG-(1-4): 119 +/- 24 fmol x mg(-1) x min(-1); P < 0.05 vs. ACE or ACE2]. Urinary metabolism of ANG I and ANG II was similar to the proximal tubules; soluble ACE2 activity was also detectable in sheep serum. In conclusion, sheep tissues contain abundant ACE2 activity that converts ANG II to ANG-(1-7) but does not participate in the processing of ANG I into ANG-(1-9).
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PMID:Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. 1689 85

The early and long-term effects of coronary artery ligation on the plasma and left ventricular angiotensin-converting enzyme (ACE and ACE2) activities, ACE and ACE2 mRNA levels, circulating angiotensin (Ang) levels [Ang I, Ang-(1-7), Ang-(1-9), and Ang II], and cardiac function were evaluated 1 and 8 weeks after experimental myocardial infarction in adult Sprague Dawley rats. Sham-operated rats were used as controls. Coronary artery ligation caused myocardial infarction, hypertrophy, and dysfunction 8 weeks after surgery. At week 1, circulating Ang II and Ang-(1-9) levels as well as left ventricular and plasma ACE and ACE2 activities increased in myocardial-infarcted rats as compared with controls. At 8 weeks post-myocardial infarction, circulating ACE activity, ACE mRNA levels, and Ang II levels remained higher, but plasma and left ventricular ACE2 activities and mRNA levels and circulating levels of Ang-(1-9) were lower than in controls. No changes in plasma Ang-(1-7) levels were observed at any time. Enalapril prevented cardiac hypertrophy and dysfunction as well as the changes in left ventricular ACE, left ventricular and plasmatic ACE2, and circulating levels of Ang II and Ang-(1-9) after 8 weeks postinfarction. Thus, the decrease in ACE2 expression and activity and circulating Ang-(1-9) levels in late ventricular dysfunction post-myocardial infarction were prevented with enalapril. These findings suggest that in this second arm of the renin-angiotensin system, ACE2 may act through Ang-(1-9), rather than Ang-(1-7), as a counterregulator of the first arm, where ACE catalyzes the formation of Ang II.
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PMID:Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. 1690 57

The renin-angiotensin system is a key regulator of blood pressure (BP), with inhibitors of angiotensin-converting enzyme (ACE) used clinically to treat hypertension and other cardiovascular conditions. ACE2 is a newly identified member of this system, which converts angiotensin II to angiotensin, and of which the occurrence in plasma has not been investigated. The aim of this study was to determine the heritability of circulating ACE, ACE2, and neprilysin (NEP), which may also be a regulator of BP, in a family study, and to determine covariates that contribute to the variation in plasma activity. ACE, ACE2, and NEP activities were measured in plasma from 534 subjects in the Leeds Family Study using selective fluorogenic substrates. Genetic factors accounted for 24.5%, 67%, and 22.7% of the phenotypic variation in circulating ACE, ACE2, and NEP, respectively. ACE insertion/deletion polymorphism and other measured covariates accounted for 23.8% of variance in circulating ACE. High-density lipoprotein cholesterol was a significant determinant of circulating ACE2. Measured covariates accounted for 17.3% of variation in circulating NEP. ACE and NEP were associated with systolic and diastolic BP in univariate analyses; however, only ACE was independently associated with systolic and diastolic BP after accounting for covariates and shared childhood household.
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PMID:Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. 1700 Sep 27

Angiotensin II (Ang II), a bioactive peptide of the renin-angiotensin system (RAAS), plays an important role in the development of cardiovascular diseases (CVD). Pharmacological inhibition of angiotensin-converting enzyme (ACE), the Ang II forming enzyme, or specific blockade of Ang II binding to angiotensin type 1 receptor (AT1R) through which it exerts its deleterious effects, were shown to provide some protection against progression of CVD. The ACE-Ang II-AT1R axis has been challenged over the last few years with RAAS components able to counterbalance the effects of the main axis. The ACE homologue ACE2 efficiently hydrolyses Ang II to form Ang (1-7), a peptide that exerts actions opposite to those of Ang II. In contrast to the Ang II axis, the role of the ACE2-Ang (1-7) axis in cardiac function is largely obscure. Ang (1-7) is present in the viable myocardium, and its formation depends on Ang II as a substrate. The expression of this peptide is associated with cardiac remodeling: it is lost in the infarcted area and significantly increased in the border area. Low doses of Ang (1-7) improve cardiac output and antagonize Ang II-induced vasoconstriction. The type of Ang (1-7) biological activity is tissue specific and dose dependent. These findings point to a possible protective role for Ang (1-7) in abating the Ang II-induced actions. The elevated expression of Ang (1-7) in failing heart tissue paralleled the expression of its forming enzyme, ACE2. Several observations and experimental evidence suggest a beneficial role for ACE2 in cardiovascular function. Elevated ACE2 expression at the initial stage of several pathologies which decline with progression of disease might indicate a protective role for ACE2. Genetic manipulation of ACE2 expression, either targeted disruption or overexpression, point to the possible significance of this enzyme in cardiac function. Based on the above, a therapeutic approach that will amplify the ACE2-Ang (1-7) axis could provide further protection against the development of CVD. It turns out that the merits of currently used drugs--ACE inhibitors, AT1R blockers and mineralocorticoid receptor blockers (MRB) - lay beyond their direct effects on suppression of the ACE-Ang II-AT1R axis as they also increase cardiac ACE2 and Ang (1-7) significantly.
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PMID:ACE2 of the heart: From angiotensin I to angiotensin (1-7). 1704 3


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