Bruno Baudin
New Aspects on Angiotensin-Converting Enzyme: from Gene to Disease
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.
Clinical Chemical Laboratory Medicine, Walter de Gruyter
Print ISSN: 1434-6621
Volume: 40, 04/2002
Pages: 256 - 265
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