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Home , Angiotensin, Chymase, Pepstatin

Journal of Human Hypertension (2000) 14, 373–376  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh REVIEW ARTICLE Chymase-dependent II formation in human blood vessels

AH Chester and JAA Borland Department of Cardiothoracic Surgery, National & Institute, Imperial College of Science Technology & Medicine, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UK

Keywords: angiotensin II; chymase

Introduction studies have identified chymase as an cap- able of angiotensin II formation in these tissues. Pharmacological modulation of the -angioten- Chymase is a N-glycosylated 30 KDa monomeric sin pathway has been shown to be of benefit in a -like enzyme, and is synthesised and number of cardiovascular diseases.1–4 The mainstay stored in granules within mast cells of the MCTC of this therapeutic strategy is to block the formation (skin) phenotype.23 The enzyme can be of effector , angiotensin II, by inhibition of inhibited by the broad spectrum angiotensin-converting enzyme (ACE). However, inhibitors soyabean inhibitor, chymostatin angiotensin II levels have been shown to return to and phenylmethylsulfonyl fluoride, but not by other pre-treatment levels following chronic ACE inhibi- protease inhibitors such as EDTA, and tor therapy, and reductions in greater aprotinin.24 In a similar fashion to chymotrypsin, than those observed with ACE inhibitors alone can chymase hydrolyses peptide bonds at the COOH-ter- be obtained by co-administration of angiotensin 5,6 mini of hydrophobic aromatic residues. The degree receptor antagonists with an ACE inhibitor. In of selectivity over which amino acids are hydro- addition, increases in plasma angiotensin II follow- lysed is a function of the extended substrate binding ing exercise or during ischaemic conditions could 7,8 site of the chymase molecule. Thus, human chymase not be prevented by an ACE inhibitor. The con- can form angiotensin II by cleavage of the Phe8-His9 cept of alternative pathways for angiotensin II for- bond of the precursor molecule, but it is unable to mation is supported by a number of in vivo and in inactivate angiotensin II since its does not cleave the vitro experiments. For example, ACE inhibitors Tyr4-Ile5 bond in angiotensin II. It is also inactive alone have been shown to be unable to completely against , , vasoactive intesti- block angiotensin II generation in the human heart nal peptide, lutenizing -releasing hormone, and detrusor muscle or block the contractile effect 9–12 and alpha-melanocyte-stimulating hor- of angiotensin I in isolated blood vessels. These mone.24 In contrast, rat chymase-1, as well as for- observations suggest the existence of alternative ming angiotensin II from angiotensin I, will also angiotensin II formation pathways which may limit form inactive fragments from angiotensin I and inac- the clinical efficacy of ACE inhibitor therapy. tivate angiotensin II. Human chymase has been located in the interstitium of the heart, in mast cells, Alternative angiotensin II generating mesenchymal interstitial cells and in endothelial cells. High levels of chymase activity are present in the human uterus, oesophagus, stomach and skin, A number of enzymes for which angiotensin I may while moderate levels can be found in tissue from act as a substrate have been identified. These the lung, colon, tonsils, adenoids, renal cortex as include tryptensin, G, tonin, , well as the left and right ventricles.25 13–18 neutralendopeptidase and chymase. The There are additional enzymes present in mast capacity to generate angiotensin II via an ACE-inde- cells that can generate angiotensin II. , pendent mechanism has been demonstrated in the found in leukocytes as well as mast cells cleaves the human myocardium, coronary arteries, internal same bond in the angiotensin molecule as ACE and mammary arteries, saphenous veins, radial arteries 11,12,19–22 chymase and subsequently generates angiotensin and gastroepiploic arteries. Many of these II.14 Another enzyme present in mast cells is the metalloprotease, carboxypeptidase A enzyme. This enzyme cleaves the His9-Leu10 bond in angiotensin I Correspondence: Adrian H Chester, Department of Cardiothoracic Surgery, National Heart & Lung Institute, Imperial College of and as a result generates the fragment angiotensin1–9, Science Technology & Medicine, Heart Science Centre, Harefield which although capable of inhibiting ACE, has no Hospital, Harefield, Middlesex, UK known intrinsic contractile activity.26 The human Chymase-dependent angiotensin II formation AH Chester and JAA Borland 374 heart has been shown to possess carboxypeptidase necrosis, intimal proliferation and the formation of 38,39 A activity, generation of angiotensin1–9 by this hyperplastic lesions. Contraction of vasa vaso- enzyme is sufficient to block cardiac ACE.27 It is rum by locally formed angiotensin II in the undetermined if human blood vessels also exhibit adventitia may initiate pathological changes in the cardoxypeptidase A activity, or if endogenous local vessel wall. In diseased coronary arteries, exhibiting ACE activity in the vessel wall is regulated by the early and intermediate atherosclerotic lesions, ACE synthesis of angiotensin1–9. Other angiotensin frag- was detected largely in regions of fat laden macro- ments may be generated by the action of neutral phages and in association with T-lymphocytes. In 24.11 and propyl-endopeptidase very diseased lesions, ACE and angiotensin II were 24.26.28 Both of these enzymes are capable of for- localised to endothelial cells lining the micro ves- 40 ming angiotensin1–7 from angiotensin I. It has been sels impregnating the plaque. It has been suggested shown that angiotensin1–7 possesses the ability to that angiotensin II formed due to the presence of stimulate the release of vasodilator prostanoids and ACE in areas of inflammation, may contribute to the nitric oxide, as well as inhibiting proliferation of pathophysiology of coronary artery disease. In vascular smooth muscle cells in balloon injured addition, mast cells have been shown to accumulate carotid arteries and rat aorta.29–31 at the site of atherosclerotic lesions in human blood Angiotensin II may also be generated via the vessels.41 Mast cell degranulation and activation is action of tonin. Tonin, a kallikrenin-like protease evident at the site of advanced lesions in which fis- has the ability to form angiotensin II from angioten- suring, haemorrhage and thrombus formation is evi- sin I as well as directly from the synthetic renin sub- dent. Up to 95% of mast cells present within these strate and from human angiotensinogen.32,33 Tonin regions contained both and chymase. is normally inactivated in plasma by the endogen- ous inhibitor alpha1-macroglobulin, however, it has Role of chymase in disease recently been shown that even when bound to alpha1-macroglobulin, tonin can still generate angio- There are conflicting reports as to the relative contri- tensin II, which is resistant to ACE inhibition.34 butions of ACE and chymase in angiotensin II forma- tion in the human heart.18,42 In vitro studies have Chymase activity and localisation in shown chymase to be responsible for up to 80% of cardiac angiotensin II formation. In contrast, in vivo human blood vessels experiments have shown ACE to be the predominant It has been shown in a number of human blood ves- angiotensin II forming enzyme.43 Data from vascular sels that angiotensin I has a similar contractile effect tissues have shown that human arteries and veins as angiotensin II. In the saphenous vein, IMA, coron- possess ACE activity to varying degrees,44 and that ary artery, gasteroepiploic artery, and radial artery chymase or chymase-like enzymes, as well as ACE, the contractions observed to angiotensin I persist in are responsible for the conversion of angiotensin I the presence of an ACE inhibitor.11,12,20,35 Incubation into the active peptide.11,12,20,35 Human atheroscler- of these vessels with the chymase inhibitors soya- otic lesions contain many chymase containing mast bean (SBTI) or chymostatin, also cells, whose activity and number increase with the fails to inhibit the response to angiotensin I. Dual severity of the lesion.45 It is thought that exocytosed inhibition of both enzymes is required before any heparin-bound chymase released by mast cells may significant inhibitory effect is observed. This has then participate in the early and late development lead to the suggestion that both ACE and chymase of atherosclerotic lesions. In addition, mast cells have the capacity to generate angiotensin II in the may also play a role in the conversion of macro- vessel wall, but that the substrate, angiotensin I may phages into cholesterol loaded foam cells. Lesion be shunted between the enzymes when one or the stability may also be affected by mast cells due to other has been inhibited.11,12 This mechanism may their ability to degrade apolipoproteins A and B of explain why plasma angiotensin II concentrations HDL and LDL respectively.45 Chymase activity and remain elevated during long term ACE inhibition. mRNA expression is increased following balloon ACE has been demonstrated to be present princi- injury to dog carotid artery and in atherosclerotic pally on the vascular endothelial cells of the lumen monkey coronary arteries.46,47 The subsequent neo- and vasa vasorum and to a lesser extent in the intimal formation following balloon injury to dog medial smooth muscle cells. In contrast, chymase carotid arteries can be inhibited by tranilast, a com- has been shown to be present in adventitial mast pound that stabilises mast cells.46 These findings are cells.11 Despite the different locations of each of of interest in light of the failure of ACE inhibitors these, they both may have the capacity to contribute to prevent restenosis following percutaneous trans- towards pathological changes within the vessel wall. luminal coronary angioplasty (PTCA) in humans.48 It has also been shown that in isolated human coron- Experimental data from rats had suggested that ACE ary arteries the angiotensin II synthesised by the inhibitors would be of benefit following PTCA. action of chymase is rapidly bound to AT1 recep- However, it is now known that the rat forms angio- tors.36 The supply of blood to the vessel wall from tensin II almost exclusively via ACE, with little con- the adventitial surface has been shown to be tribution from enzymes such as chymase. of importance.37,38 A number of different animal There is also evidence that other angiotensin II models of rely on rendering the ves- forming enzymes are active in vivo. Exercise- sel wall hypoxic via the occlusion of the vasa vaso- induced angiotensin II release in healthy volunteers rum, which results in the initiation of medial can be inhibited by the serine protease inhibitor

Journal of Human Hypertension Chymase-dependent angiotensin II formation AH Chester and JAA Borland 375 nafamostat.8 This drug is also beneficial in patients antagonism on blood pressure and renin release in with peripheral vascular disease.7 It was originally -depleted normotensives. Circulation 1995; 92: thought that nafamostat could block the effect of 825–834. chymase, however, it is now claimed that this 6 Mento PF, Wilkes BM. Plasma and blood inhibitor has no activity against chymase or ACE. pressure during converting enzyme inhibition. Hyper- tension 1987; 9: III42–III48. Thus the effect of nafamostat may be attributable to 7 Urabe Y et al. Beneficial effects of a serine protease its effect on nafamostat-sensitive serine protease(s) inhibitor in peripheral vascular disease. Am J Cardiol such as kallilerin and cathepsin G. 1993; 72: 218–222. 8 Miura S et al. Angiotensin II formation by an alterna- tive pathway during exercise in humans. 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