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To Endothelin-1-(1-21) in Vitro (Cardiovascular/Vasoconstriction/Vascular Endothelium/Metafloprotease/Endothelin-Converting Enzyme) ELLEN G

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To Endothelin-1-(1-21) in Vitro (Cardiovascular/Vasoconstriction/Vascular Endothelium/Metafloprotease/Endothelin-Converting Enzyme) ELLEN G Proc. Natl. Acad. Sci. USA Vol. 88, pp. 703-707, February 1991 Physiology/Pharmacology Phosphoramidon blocks the pressor activity of porcine big endothelin-1-(1-39) in vivo and conversion of big endothelin-1-(1-39) to endothelin-1-(1-21) in vitro (cardiovascular/vasoconstriction/vascular endothelium/metafloprotease/endothelin-converting enzyme) ELLEN G. MCMAHON*t, MARIA A. PALOMO*, WILLIAM M. MOOREt, JOHN F. MCDONALDt, AND MICHAEL K. STERNt *Searle Research and Development, GD Searle & Co. and tMonsanto Corporate Research, Monsanto Company, 800 North Lindbergh Boulevard, St. Louis, MO 63167 Communicated by Philip Needleman, October 12, 1990 (receivedfor review July 2, 1990) ABSTRACT In porcine aortic endothelial cells, the 21- Serine-, cysteinyl-, aspartyl-, and metalloproteases have all amino acid peptide endothelin-1 (ET-1) is formed from a 39- been identified as processing enzymes responsible for the amino acid intermediate called "big endothelin-1" (big ET-1) by conversion of precursor proteins to bioactive peptides in a putative ET-converting enzyme (ECE) that cleaves the 39-mer mammalian cells (9). In their original report on the isolation at the bond between Trp-21 and Val-22. Since big ET-1 has only and characterization of ET, Yanagisawa and coworkers (1) 1/100-1/150th the contractile activity of ET-1, inhibition of speculated that ECE is a serine protease with a chymotrypsin- ECE should effectively block the biological effects of ET-1. Big like specificity. Furthermore, we demonstrated that chymo- ET-1 injected intravenously into anesthetized rats produces a trypsin can produce ET-1 from big ET-1, although cleavage at sustained pressor response that presumably is due to conversion Tyr-31 also occurred (10). Ohlstein and coworkers (11) re- of big ET-1 into ET-1 by ECE. We determined the type of ported that two chymotrypsin inhibitors [L-1-tosylamido-2- protease activity responsible for this conversion by evaluating phenylethyl chloromethyl ketone (TPCK) and isatoic anhy- the effectiveness of protease inhibitors in blocking the pressor dride] decreased the amount of ET produced by bovine aortic response to big ET-1 in ganglion-blocked anesthetized rats. The endothelial cells in culture, whereas phenylmethylsulfonyl serine protease inhibitor leupeptin, the cysteinyl protease inhib- fluoride and chymostatin did not block ET production. It is not itor E-64, and the metalloprotease inhibitors captopril and clear from these studies whether ECE is a serine protease or kelatorphan were all ineffective at blocking the pressor response whether other enzymes involved in the processing of prepro- to big ET-1. However, the metalloprotease inhibitors phos- ET are sensitive to inhibition by certain serine protease phoramidon and thiorphan dose-dependently inhibited the pres- et al. (12) that sor response to big ET-1, although phosphoramidon was sub- inhibitors. Recently, Takaoka demonstrated stantially more potent than thiorphan. None of the inhibitors pepsin, an aspartyl protease, cleaves big ET-1 specifically at blocked the pressor response to ET-1 and none had any effect on the bond between Trp-21 and Val-22, although this conversion mean arterial pressure when administered alone. In a rabbit occurred at pH 2.3. Matsumura et al. (13) have further shown lung membrane preparation, ECE activity was identified that that a pepstatin-sensitive enzyme activity in an extract from was blocked by the metalloprotease inhibitors phosphoramidon cultured porcine aortic endothelial cells converts big ET-1 to and 1,10-phenanthroline in a concentration-dependent manner. ET-1. However, the physiological relevance of this conver- This enzyme converted big ET-1 to a species of ET that comi- sion, which occurs only at acidic pH, is not known. More grated on HPLC with ET-1 and produced an ET-like contraction recently, Nichols et al. (14) suggested that ECE is a cysteinyl in isolated rat aortic rings. Our results suggest that the physi- protease, while Ohnaka and coworkers (15) reported that ECE ologically relevant ECE is a metalloprotease. is an EDTA-sensitive neutral metalloprotease. Our strategy to determine the type of protease activity In 1988, Yanagisawa and coworkers (1) reported on the responsible for the conversion ofbig ET-1 to ET-1 in vivo was isolation and characterization of a peptide, endothelin (ET), to evaluate the effectiveness of different classes of protease from the culture supernatant of porcine aortic endothelial inhibitors in blocking the pressor response to big ET-1 injected cells. Now referred to as endothelin-1 (ET-1), this peptide intravenously into ganglion-blocked anesthetized rats. In this contracts vascular smooth muscle in vitro and produces a model, big ET-1 produces a sustained pressor response which sustained pressor response in vivo. In porcine aortic endothe- presumably is due to the conversion of big ET-1 to ET-1 by lial cells, the 21-amino acid peptide ET-1 is formed from a ECE. Our in vivo results indicate that the enzyme responsible 39-amino acid intermediate called "big endothelin-1" (big for the pressor activity of big ET-1 is a metalloprotease ET-1) by a putative ET-converting enzyme (ECE) that hydro- because this activity is blocked by the metalloprotease inhib- lyzes the 39-mer at the bond between Trp-21 and Val-22 to itors phosphoramidon and thiorphan. Furthermore, we have yield ET-1-(1-21) and the C-terminal fragment, big ET-1-(22- partially purified an ECE from rabbit lung membranes. This 39) (2). Since big ET-1 has only 1/100-1/150th the contractile enzyme converts big ET-1 to a molecular species that comi- activity ofET-1 (3), inhibition ofECE should effectively block grates with ET-1 on HPLC and produces an ET-like contrac- the biological effects of ET-1. This could be an important tion in isolated vascular smooth muscle. This conversion is therapeutic strategy for the treatment of hypertension, acute also blocked by the metalloprotease inhibitors phosphorami- renal failure, myocardial infarction, and coronary and cerebral don and 1,10-phenanthroline. Our results suggest that the vasospasm-diseases in which an overproduction ofET might physiologically relevant ECE is a metalloprotease. play an important pathophysiological role (4-8). Abbreviations: ET, endothelin; ECE, ET-converting enzyme; MAP, The publication costs of this article were defrayed in part by page charge mean arterial pressure; NEP, neutral endopeptidase EC 3.4.24.11 payment. This article must therefore be hereby marked "advertisement" (enkephalinase). in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 703 Downloaded by guest on October 1, 2021 704 Physiology/Pharmacology: McMahon et al. Proc. Natl. Acad. Sci. USA 88 (1991) MATERIALS AND METHODS delivery system. A 5-,um Vydac C18 column was used to In Vivo Experiments. Male Sprague-Dawley rats (200-250 separate big ET-1 from ET-1. Elution was performed by using g) were anesthetized with Inactin (100 mg/kg of body weight a binary gradient consisting of 0.02% CF3COOH in water i.p.), and catheters (PE-50) were inserted in a femoral artery (solvent A) and 0.02% CF3COOH in acetonitrile (solvent B). and vein for measurement of mean arterial pressure (MAP) The elution profile incorporated a linear gradient from 0 to and administration of drugs, respectively. Autonomic neu- 35% solvent B in 15 min followed by isocratic elution at 35% rotransmission was blocked by treatment with mecamyl- solvent B for 15 min and a linear gradient from 35% to 63% amine (3 mg/kg i.v.) and atropine (400 pg/kg i.v.). The rats solvent B over 15 min at a flow rate of 0.5 ml/min. Eluates were allowed to recover for 45 min after implantation of the were monitored by absorbance at 215 nm. With this system, catheters. Subsequently, either big ET-1 or ET-1 at 1 nmol/ big ET-1 and ET-1 were completely resolved with retention kg with or without protease inhibitor, or protease inhibitor times of 34.3 and 36.8 min, respectively. alone, was administered i.v. Various amounts of protease HPLC assays to monitor the conversion of big ET-1 to inhibitors were administered as an i.v. bolus 10-15 sec prior ET-1 used the soluble enzyme fraction prepared as described to the administration of big ET-1 or ET-1. above but with further purification by ammonium sulfate Porcine big ET-1-(1-39) and both human and porcine fractionation. Thus, in a typical example, a 10-ml aliquot of ET-1-(1-21) were obtained from Peptides International (Lou- the soluble enzyme fraction was brought to 33% saturation in isville, KY) and were serially diluted from 100 ,uM stock ammonium sulfate, equilibrated for 30 min, and centrifuged solutions (in distilled water) with 0.05% bovine serum albu- at 11,000 x g for 20 min. The supernatant was brought to 65% min in 0.9%o saline. Leupeptin, phosphoramidon, and E-64 saturation and then centrifuged at 11,000 x g for 20 min. The were obtained from Peptides International, and captopril was resulting pellet was dissolved in 4.0 ml of50mM Tris'HC1 (pH a gift from Squibb. Racemic thiorphan {(±)-N-[1-oxo-2- 7.5) and was dialyzed against the same buffer for 12 hr. This (mercaptomethyl)-3-phenyl-propyl] glycine} was synthesized enzyme preparation had a total protein concentration of 2.4 by a modification of previously described procedures (16, mg/ml and contained ECE activity as monitored by the rat 17). Kelatorphan {(R,S)-[3-(N-hydroxy)carboxamido-2- aortic ring assay. benzylpropanoyl]-L-alanine} was synthesized by the method The conversion of big ET-1 to ET-1 was demonstrated by of Fournie-Zaluski et al.
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