(Hypertension. 1998;31:362.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Metabolism of Angiotensin-(1–7) by Angiotensin-Converting Enzyme
From the Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Correspondence to Mark C. Chappell, Hypertension Center, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1095. E-mail mchappel{at}bgsm.edu
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Abstract |
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Angiotensin converting enzyme (ACE) inhibitors augment circulating levels of the vasodilator peptide angiotensin-(1–7) [Ang-(1–7)] in man and animals. Increased concentrations of the peptide may contribute to the antihypertensive effects associated with ACE inhibitors. The rise in Ang-(1–7) following ACE inhibition may result from increased production of the peptide or inhibition of the metabolism of Ang-(1–7)-similar to that observed for bradykinin. To address the latter possibility, we determined whether Ang-(1–7) is a substrate for ACE in vitro. In a pulmonary membrane preparation, the ACE inhibitor lisinopril attenuated the metabolism of low concentrations of 125I-Ang-(1–7). The primary product of 125I-Ang-(1–7) metabolism was identified as Ang-(1–5). Using affinity-purified ACE from canine lung, HPLC separation and amino acid analysis revealed that ACE functioned as a dipeptidyl carboxypeptidase cleaving Ang-(1–7) to the pentapeptide Ang-(1–5). The ACE inhibitors lisinopril and enalaprilat (1 µmol/L), as well as the chelating agents EDTA, o-phenanthroline, and DTT (0.1-1 mmol/L) abolished the generation of Ang-(1–5) and did not yield other metabolic products. Ang-(1–5) was not further hydrolyzed by ACE. Kinetic analysis of the hydrolysis of Ang-(1–7) by ACE revealed a substrate affinity of 0.81 µmol/L and maximal velocity of 0.65 µmols min-1 mg-1. The calculated turnover constant for the peptide was 1.8 sec-1 with a catalytic efficiency (Kcat/Km) of 2200 sec-1mmol/L-1. These findings suggest that increased levels of Ang-(1–7) following ACE inhibition may due, in part, to decreased metabolism of the peptide.
Key Words: angiotensin-converting enzyme • dipeptidyl carboxypeptidase • Ang-(1–7) • Ang-(1–5) • lisinopril • enalaprilat
Abbreviations: ACE = angiotensin converting enzyme • Ang = angiotensin • DNFB = 1-fluro-2,4-dinitroflurobenzene • DTT = dithiothreitiol • EDTA = ethylene diaminetetraacetic acid • HPLC = high performance liquid chromatography • kcat = catalytic constant • kcat/Km = specificity constant • Ki = inhibitory constant • Km = affinity constant • SHR = spontaneously hypertensive rat • Vmax = maximal velocity • WKY = Wistar-Kyoto • ZPP = Z-prolyl prolinal
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Introduction |
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The vasodilator peptide angiotensin-(1–7) [Ang-(1–7)] is one of several alternative products of the renin-angiotensin system. In contrast to Ang II, the cumulative effects of Ang-(1–7) suggest an antihypertensive role for the heptapeptide.1 Ang-(1–7) exhibits potent natriuretic and diuretic actions in the kidney2–4 and vasodepressor effects in the coronary and mesenteric vascular beds.5–7 Santos and colleagues have recently reported that low concentrations of Ang-(1–7) enhance the vasodepressor actions of bradykinin.8 Treatment with angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase EC 3.4.15.1) inhibitors augment peptide levels substantially (5–25 fold) in the circulation of several species including man.9–13 These results suggest that in addition to decreased production of Ang II and enhanced levels of bradykinin, increased concentrations of Ang-(1–7) may potentially contribute to the beneficial actions of ACE inhibitors. Indeed, acute treatment with an Ang-(1–7) monoclonal antibody partially reverses the antihypertensive effects of combined lisinopril/losartan treatment in SHR rats.14
At present, little is known regarding the enzymes involved in the metabolism of circulating and tissue Ang-(1–7). Although a number of enzymes are capable of processing either Ang I or Ang II to Ang-(1–7),15 neprilysin (EC 3.4.24.11) appears to be a candidate enzyme responsible for the production of circulating Ang-(1–7) in rat. Neprilysin is an endopeptidase which converts Ang I directly to Ang-(1–7) and is primarily situated on the surface of both endothelial and epithelial cells.15 Infusion of the selective neprilysin inhibitor SCH 39370 abolished circulating levels of Ang-(1–7) in SHR and WKY rats treated with the ACE inhibitor enalaprilat.16 Much less is known of the enzymes which participate in the degradation of Ang-(1–7). In this regard, we examined whether the peptide is a suitable substrate for ACE since inhibition of the enzyme augments both circulating and tissue levels of Ang-(1–7).
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Methods |
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ACE Purification
ACE was purified from a membrane fraction of canine lung using a lisinopril-coupled affinity column.17,18 Membranes were prepared from frozen lung (stored at (80°C) by homogenizing the tissue (1:10 wt/vol) in 25 mmol/L HEPES, 0.2 mol/L NaCl, pH 8.0 (Buffer A) in a blender followed by centrifugation at 10 000 g for 30 minutes at 4°C. Purified ACE was analyzed by SDS-polyacrylamide gel electrophoresis (6% polyacrylamide, wk/v) using the stacking method described by Laemmli.20 SDS-polyacrylamide electrophoresis of the purified ACE revealed a single protein band with a molecular size of 170,000 daltons, which is essentially identical to that reported for ACE (160-180 000 daltons) in various species by other investigators.15,18,19,21,22 Proteins were visualized with a Pharmacia silver stain kit (Pharmacia Biotech) based on the method of Heukeshoven.23 Protein concentration was determined with a Bradford protein assay kit using a BSA standard (BioRad).
Assays
Metabolism of 125I-Ang-(1–7) was determined in pulmonary membranes prepared by homogenization of canine lung tissue (1:10 wt/vol, previously frozen at -80°C) in 20 mmol/L HEPES, 300 mmol/L mannitol pH 7.4 and centrifuged at 30 000g for 20 minutes at 4°C. The resultant pellet was homogenized again in the HEPES buffer with a Potter-Elverjhem Teflon pestle and re-centrifuged. The metabolism assay contained 10 µg protein of pulmonary membrane and 5 nmol/L 125I-Ang-(1–7) in a volume of 0.1 mL with or without 10 µmol/L lisinopril. The reaction was terminated with 80% acetonitrile/0.4% phosphoric acid and stored at -80°C until HPLC analysis (see below).
ACE activity was routinely determined using the synthetic substrate Hip-His-Leu (Sigma, St. Louis MI) as described previously.24 The effect of Ang-(1–7) or bradykinin (all peptides from Bachem Torrance) to inhibit ACE activity was determined from Lineweaver-Burke plots of the reaction velocity versus the substrate concentration with and without the peptide. The apparent Km (Km') was determined in the presence of the inhibitor (I) and the Ki was determined based on the relationship Km'=Km(1+[I]/Ki). For the kinetic assays, 40 ng of ACE was incubated with 0.1 to 2.0 µmol/L of Ang-(1–7) for 30 minutes at 37°C in 5.0 mL of 10 mmol/L HEPES, 125 mmol/L NaCl, pH 7.4. The Km and Vmax constants for the hydrolysis of Ang-(1–7) were determined from Lineweaver Burke plots using the GraphPad Prism plotting and statistical package (GraphPad). The reaction was terminated with 0.5 mL 1% HFBA and the peptides concentrated on a Bond Elute C18 column (Varian) as described.25 As an internal standard, 10 000 cpm of 125I-Ang-(1–7)(2200 Curies/ mmol) was added to the samples before the extraction step. Substrate disappearance and product formation were determined by HPLC separation and UV detection at 220 nM (see below).
HPLC Analysis
Separation of the Ang-(1–7) and Ang-(1–5) was achieved by HPLC using a heptafluorobutyric acid (HFBA, Sequanal Grade, Pierce) solvent system performed under isocratic conditions of 27% mobile phase B at a flow rate of 0.35 mL/min at ambient temperature.26 Peptides were monitored at 220 nm (ABI 783 Spectroflow detector) with a PC Chrom 24 bit data acquisition system (H&S Scientific). The peak of Ang-(1–5) derived from the ACE hydrolysis was also collected for amino acid analysis. Chromatographic separation of 125I-Ang-(1–7) and metabolites were achieved with 0.1% phosphoric acid (PHOS, mobile phase A) and 80% ACN/0.1% PHOS (mobile phase B). The gradient consisted of 15% B for 2 minutes; 15%–30% B linear for 15 minutes and 30% B for 10 minutes at a flow rate of 0.3 mL/min at ambient temperature. HPLC fractions were collected at 1 minute intervals and counted in a gamma counter.
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Results |
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We initially assessed the metabolism of 125I-Ang-(1–7) in pulmonary membranes—a source of high peptidase activity. As shown in Fig 1 (upper figure), the time course reveals that 125I-Ang-(1–7) was essentially metabolized in 30 minutes by peptidase activity associated with the pulmonary membranes. Addition of the selective ACE inhibitor lisinopril (10 µmol/L) attenuated the metabolism of Ang-(1–7) and shifted the disappearance curve of the peptide to the right (Fig 1). In this preparation, the degree to which lisinopril inhibits the degradation of Ang-(1–7) suggests a primary role for ACE in the peptide’s metabolism. As shown in the lower panel of Figure 1, the HPLC chromatograph of a 15 minutes incubation period reveals that the major 125I-metabolite peak corresponds to Ang-(1–5). Although not shown, lisinopril abolished the peak of 125I-Ang-(1–5) and increased the radioactive peak corresponding to 125I-Ang-(1–7) at the 15 and 30 minutes time periods.
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To further characterize the hydrolysis of Ang-(1–7), we incubated affinity-purified ACE with the peptide (100 µmol/L) for 60 minutes at 37°C and analyzed the product(s) by HPLC. As shown in the chromatograph of Fig 2 (left panel: Control), Ang-(1–7) was converted by ACE to a peptide eluting at a retention time corresponding to the peptide standard Ang(1–5). Note that the HPLC separation of unlabeled peptides with the HFBA counter-ion reverses the elution pattern of Ang-(1–5) and Ang-(1–7) as compared to the separation of 125I-peptides with phosphoric acid (Fig 1 chromatograph). The amino acid analysis of the peak resulting from the hydrolysis of Ang-(1–7) confirmed its identity as the pentapeptide Ang-(1–5). The dipeptide product His-Pro, which also results from the hydrolysis of Ang-(1–7), elutes quite early under these chromatographic conditions and is effectively buried in the void volume peak. As shown in the middle panel of Fig 2 (+Lisinopril), addition of the selective ACE inhibitor lisinopril (1 µmol/L) inhibited (>95%) the generation of Ang-(1–5). The addition of the chelating agent EDTA (1 mmol/L) abolished the conversion of Ang-(1–7) to Ang-(1–5) (Fig 2 right panel, +EDTA). The inhibitors lisinopril or EDTA did not reveal additional proteolytic products derived from Ang-(1–7) and both agents increased the peak of Ang-(1–7) virtually to its original concentration prior to hydrolysis. The control chromatograph (Fig 2, left panel) also did not reveal hydrolysis of Ang-(1–5) by ACE—the Ang-(1–5) product accounted for essentially all the hydrolyzed substrate. Furthermore, as shown in the left panel of Fig 3, incubation of Ang-(1–5) with ACE under identical conditions to that for Ang-(1–7) demonstrated no detectable hydrolysis of the pentapeptide. The addition of lisinopril (Fig 3, right panel, +Lisinopril) did not increase the recovery of Ang-(1–5) as compared to the control chromatograph.
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The ability of various inhibitors to block the hydrolysis of 10 µmol/L Ang-(1–7) and the synthetic substrate Hip-His-Leu (1 mmol/L) were compared. Inhibitory agents were preincubated with the enzyme for 5 minutes at 37°C before the addition of substrate. As shown in the Table, the conversion of Ang-(1–7) to Ang-(1–5) was completely blocked with a 1 µmol/L concentration of either the selective ACE inhibitors lisinopril or enalaprilat. These inhibitors also abolished the hydrolysis of Hip-His-Leu. Since Zn+2 is an absolute requirement for ACE activity, we compared several chelating agents to inhibit Ang-(1–7) hydrolysis. The metallopeptidase inhibitors EDTA (100 µmol/L), 1, 10-O-pthenanthroline (1 mmol/L) and DTT (1 mmol/L) all abolished the conversion of Ang-(1–7) to Ang-(1–5) by ACE, as well as inhibited the hydrolysis of Hip-His-Leu. Finally, the selective inhibitors for neprilysin (SCH 39370)27 and prolyl endopeptidase and prolyl carboxypeptidase (Z-prolyl-prolinal, ZPP)28,29 did not inhibit the hydrolysis of Ang-(1–7) or Hip-His-Leu.
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To probe the site involved in Ang-(1–7) hydrolysis by ACE, we treated the enzyme with 1-fluro-2,4-dinitroflurobenzene (DNFB, Sigma) as described by Bunning et al.30 This agent labels a critical tyrosine residue in the C-terminal site of somatic and testicular ACE to inhibit activity of that site.31 Deddish et al32 have demonstrated that the N terminus of ACE is relatively resistant to DNFB inhibition. As shown in the Table, DNFB inhibited the hydrolysis of Hip-His-Leu and Ang-(1–7) to a similar extent. At the high NaCl concentrations used here, Hip-His-Leu is predominantly, if not exclusively hydrolyzed by the C domain of ACE.33 That DNFB abolished the hydrolysis of both substrates suggests that Ang-(1–7) may interact primarily with the C domain of somatic ACE.
We then determined the kinetic constants for the inhibition of ACE by Ang-(1–7) using the synthetic substrate Hip-His-Leu. We compared the potency of Ang-(1–7) to inhibit ACE to that of bradykinin—a peptide that exhibits the highest affinity for ACE among endogenous substrates. Shown in the double reciprocal plot of Fig 4 (upper panel) are the effects of either 1.0 µmol/L Ang-(1–7) or bradykinin on ACE activity with increasing concentrations of the substrate Hip-His-Leu. Both peptides inhibited the Hip-His-Leu hydrolysis. However, Ang-(1–7) exhibited a slightly lower inhibitory constant (Ki) of 0.65 µmol/L (r2=0.99) in comparison to bradykinin (Ki of 1.2 µmol/L, r2=0.99). In three experiments, the Ki’s for Ang-(1–7) and bradykinin averaged 0.75 and 1.3 µmol/L, respectively. The kinetic characteristics for the ACE-dependent hydrolysis of Ang-(1–7) were then determined by varying the concentration of peptide from 0.1 to 2 µmol/L. As shown in the lower panel of Fig 4, the double reciprocal plot for Ang-(1–7) from three experiments revealed a Km of 0.81 µmol/L and a Vmax of 0.65 µmols/min/mg protein (r = 0.98). The catalytic constant (kcat) was 1.8 sec-1 using a molecular weight of 170kD and the specificity or efficiency constant, a measure of the catalytic activity versus affinity (kcat/Km) was 2200 sec-1mmol/L-1.
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Discussion |
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In the present study, we demonstrate that Ang-(1–7) is a substrate for ACE in vitro. The enzyme behaves as a dipcptidyl carboxypeptidase to hydrolyze the isoleucine5-histidine6 bond of Ang-(1–7) to yield the pentapeptide Ang-(1–5) and the dipeptide His-Pro, but does not further cleave the pentapeptide to shorter fragments. While ACE sequentially cleaves bradykinin to bradykinin-(1–7) and bradykinin-(1–5), the enzyme does not hydrolyze the pentapeptide fragment of bradykinin.15 Although ACE is now known to hydrolyze a variety of peptides, many of these substrates display unfavorable kinetic constants requiring high substrate concentrations or necessitate unusual incubation conditions. Under the present conditions (pH 7.4, 125 mmol/L NaCl), kinetic analysis of the ACE-dependent hydrolysis of Ang-(1–7) revealed that the peptide exhibits a Km of 0.81 µmol/L, which is comparable to that of bradykinin (0.5 to 1 µmol/L).33,34 The Km for Ang-(1–7) is 10 to 200 fold less than Ang I (10–70 µmol/L), substance P (25 µmol/L) or LHRH (170 µmol/L).15,34,35 The specificity constant (kcat/Km) for Ang-(1–7) was approximately 2000 sec-1mmol/L-1. Bradykinin typically yields the highest specificity constants (5000-60 000 sec-1mmol/L-1) among endogenous substrates.34,36 In comparison, kcat/Km values are substantially less for Ang I (190 sec-1mmol/L-1), substance P (155 sec-1mmol/L-1) and LHRH (20 sec-1mmol/L-1), which primarily reflect their lower affinity values.34,35 Although the present studies do not define the in vivo role for ACE, the favorable kinetic values for Ang-(1–7) hydrolysis suggests a dual role for ACE in the processing of angiotensin peptides. As depicted in Fig 5, we speculate that ACE may be involved not only in the formation of Ang II, but possibly in the metabolism of Ang-(1–7). In the presence of an ACE inhibitor (ACEI), elevated concentrations of Ang I and attenuation of Ang-(1–7) hydrolysis may contribute to the increased levels of Ang-(1–7) in the circulation or tissue. Moreover, Iyer et al14,36 has shown that neutralization of circulating Ang-(1–7), blockade with the [Sar1,Thr8]-Ang II antagonist or neprilysin inhibition increased blood pressure in lisinopril/losartan-treated SHR. Thus, the antihypertensive actions of ACE inhibitors may encompass augmented levels of kinins and Ang-(1–7), as well as the attenuated levels of Ang II.
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Somatic ACE is an unusual enzyme in that this monomeric protein contains two similar active centers. These functionally active sites are closely homologous; both the N-terminal and C-terminal domains bind Zn+2 and various ACE inhibitors.33,34,37 Recombinant ACE studies utilizing Ang I, bradykinin, and substance P as substrates have demonstrated that the C domain of ACE is more active than the N domain.21,33 The synthetic substrate Hip-His-Leu is cleaved preferentially by the C domain at elevated chloride concentrations.33 In contrast, the peptide N-acetyl-Ser-Asp-Lys-Pro is cleaved by the N domain of somatic ACE.38 The contribution of either active site to peptide hydrolysis may be influenced by whether the enzyme is membrane bound or in a soluble form. Jaspard and Alhenc-Gelas39 reported that the N domain exhibits a higher catalytic rate for the conversion of Ang I to Ang II when ACE is expressed on the membranes of CHO cells, although the affinity for Ang I is markedly decreased for the membrane bound enzyme. The present study does not definitively establish which domain of somatic ACE participates in the hydrolysis of Ang-(1–7). Ang-(1–7) competition experiments using the Hip-His-Leu substrate yielded similar values for the inhibitory constant (Ki of 0.75 µmol/L) and the affinity constant (Km of 0.81 µmol/L). Riordan and colleagues have shown that DNFB targets an essential tyrosine residue in the C domain.30,40 Deddish et al32 have recently reported a maximal inhibition of only 30% with DNFB (10 mM) of the single N domain of ACE isolated from ileal fluid. In comparison, they observed complete inhibition (>95%) of testicular ACE, which contains only the C domain and approximately 75% inhibition of somatic ACE. That DNFB treatment completely abolished the hydrolysis of both Hip-His-Leu and Ang-(1–7) suggests that the C domain of somatic ACE may predominate.* Deddish et al41 recently reported that ACE hydrolyzes Ang-(1–7) with similar kinetic values to that of the present study. However, their findings indicate that the peptide may be preferentially cleaved by the N domain of human ACE. At this point, further studies using the testicular ACE are required to clearly establish which domain of canine somatic ACE hydrolyzes Ang-(1–7).
Several studies have revealed a potentially important interaction between Ang-(1–7) and the kinin system to mediate vascular relaxation. Both Porsti et al6 and Brosnihan et al7 showed that Ang-(1–7), but not Ang II stimulates coronary artery vasorelaxation. The Ang-(1–7)-dependent vasodilation was potentiated by an ACE inhibitor6 and blocked by the nonselective receptor antagonist [Sar1,Thr8]-Ang II7; the selective AT1 or AT2 Ang II receptor antagonists were without effect.6,7 The vasodilatory actions of Ang-(1–7) are attenuated, but not abolished by the bradykinin B2 antagonist icatibant.6,7 Additional studies now show that Ang-(1–7) can also potentiate the vasorelaxant effects of bradykinin in the intact animal8 and in isolated coronary rings.42 In the rat, indomethacin but not enalaprilat attenuated the in vivo effects of Ang-(1–7).8 In the study by Li et al,42 lisinopril blocked the potentiation of bradykinin by Ang-(1–7) and Ang-(1–7) attenuated the rate of bradykinin metabolism in coronary rings. The results of the latter study suggest that Ang-(1–7) interacts with ACE at least in vitro to influence the hydrolysis of bradykinin—a finding that is compatible with the present study demonstrating high affinity of Ang-(1–7) for ACE. However, we do not regard Ang-(1–7) as a potent inhibitor of ACE given the low endogenous concentrations of the peptide (10–50 pmol/L) and the high in vivo concentrations of the enzyme. Although the mechanism for the potentiation in the intact animal remains to be determined, the reduced metabolism of both Ang-(1–7) and bradykinin by ACE inhibition may reinforce the synergistic responses of the two peptides.
In conclusion, the present study suggests that in addition to the hydrolysis of bradykinin and Ang I, ACE may participate in the metabolism of Ang-(1–7). Accumulation of both bradykinin and Ang-(1–7) as well as the reduction in Ang II following ACE inhibition may contribute to the beneficial effects of this therapeutic agent. That ACE inhibition may reduce the metabolism of both Ang-(1–7) and bradykinin is especially intriguing given the recent observations that these peptides exhibit synergistic actions.
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Acknowledgments |
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This study was supported by grants HL-56973, T35 HL07790, and HL-51952 from the National Heart, Lung, and Blood Institute. Amino acid analysis was performed in the Protein Core Facility at the Bowman Gray School of Medicine, Wake Forest University (Dr Mark Lively, director).
Received September 17, 1997; first decision October 16, 1997; accepted October 31, 1997.
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