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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

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Volume 40, Issue 3 (Apr 2002)

Issues

New Aspects on Angiotensin-Converting Enzyme: from Gene to Disease

Bruno Baudin
Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/CCLM.2002.042

Abstract

Angiotensin-converting enzyme (ACE) is a well known zinc-metallopeptidase that converts angiotensin I to the potent vasoconstrictor angiotensin II and that degrades bradykinin, a powerful vasodilator, both for regulation of vascular tone and cardiac functions. Other natural substrates of ACE were identified broadening the functions of this enzyme within different physiological contexts such as neuronal metabolism, hematopoiesis, digestion and reproduction. Synthetic substrates were developed for the determination of ACE activity in various biological fluids, mostly human plasma, for the diagnosis of sarcoidosis and other granulomatous diseases. After the successful use of captopril, the first ACE inhibitor in the treatment of hypertension, a number of molecules were synthesized and used in the treatment of congestive heart failure and for preventing cardiac impairment after myocardial infarction. This class of antihypertensive drugs benefited from structural data on carboxypeptidases active site, as ACE molecule has not yet been crystallized. In the last two decades ACE gene has been cloned that allowed the identification (i) of two isoenzymes, one called somatic ACE resulting from gene duplication and primarily expressed in endothelial cells, and the other, called germinative or testicular ACE, resulting from the transcription in the male reproductive system of a more simple gene, (ii) of an hydrophobic C-terminal peptide for membrane-anchoring and specifically cleaved by a metalloprotease to release soluble forms of both isoenzymes, and (iii) of several allelic polymorphisms, one of them consisting of an insertion/deletion (I/D) polymorphism in a short intronic Alu sequence that could account for half the variance in plasma ACE level and resulting in a large inter- individual variability; moreover this I/D polymorphism was proposed as a genetic marker for identifying individuals at high risk of ischemic heart disease and of anticipating in one individual the efficacy of the antihypertensive therapy, although conflicting data arose from the past decade literature. Moreover, ACE gene cloning has confirmed the expression of the enzyme in endothelial cell, in particular as an ecto-enzyme facing the vascular lumen, but not to the same extent with regard to the vascular origin of the cells. Plasma ACE in healthy subjects arises essentially from the endothelium. On the other hand, in granulomatous diseases where a local stimulation of macrophages leads to an abnormal ACE secretion, it can also be found in other biological fluids such as cerebrospinal and broncho-alveolar fluids. Low plasma ACE levels result from endothelium impairment such as in deep vein thrombosis or in endothelio-toxic anticancer therapies. Another cause of low, sometimes undetectable, plasma ACE levels is the use of an ACE inhibitor, but this is without any significance with regard to its clinical benefits. Albeit molecular cloning has provided a number of new details on ACE structure and function, many questions still remain, in particular about its tertiary structure including glycosylations, about its tissue-specific expression and regulation, and also about the exact significance of the I/D polymorphism in cardiovascular pathology including the pharmacogenomic field.

About the article

Published Online: 2005-06-01

Published in Print: 2002-04-10


Citation Information: Clinical Chemistry and Laboratory Medicine, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2002.042. Export Citation

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