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Am J Physiol Heart Circ Physiol 289: H1796 –H1797, 2005;
doi:10.1152/ajpheart.00781.2005.
Editorial Focus
Novel mechanism of action of ACE and its inhibitors
Oscar A. Carretero
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan
ANGIOTENSIN-CONVERTING ENZYME
Address for reprint requests and other correspondence: O. A. Carretero,
Hypertension and Vascular Research Division, E&R 7123, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202 (e-mail: [email protected]).
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Table 1. Therapeutic effects of ACE inhibitors
Antihypertensive
Reverse left ventricular hypertrophy and vascular disease
Prevent remodeling after myocardial infarction
Slow progression of heart failure
Slow progression of renal disease (diabetes, microalbuminuria)
Prevent diabetes
Prevent cancer and slow the aging process?
In this issue of the AJP-Heart & Circulatory Physiology,
Ignjacev et al. (5) report that soluble ACE, independent of its
dipeptidyl peptidase activity, induces the transcription factor
NF-␬B and AP-1 and increases mRNA for the bradykinin B1
and B2 receptors in vascular smooth muscle cells. This is the
second report showing that ACE has effects that are independent of its dipeptidyl peptidase activity. Recently, Kondoh et
al. (9) described a novel glycosyl phosphatidylinositol (GPI)anchored, protein-releasing activity of ACE by cleavage at the
mannose-mannose linkage site. This GPIase activity was
weakly inhibited by tightly binding ACE inhibitors and was not
inactivated by substituting the core amino acid residues necessary for peptidase activity. Taken together with Ignjacev’s
study, this suggests that neither of the two peptidase catalytic
domains of ACE is responsible for ACE GPIase activity or
induction of the transcription factor and mRNA for the B1 and
B2 receptors. Thus in addition to its classical catalytic domain
with peptidase activity, ACE may have other novel active
catalytic domains, or it may act as an agonist for some receptor
or via yet another undetermined mechanism (Fig. 2). The
Fig. 1. Effect of angiotensin-converting enzyme (ACE) due to its dipeptidyl
peptidase activity, and possible mechanism of action of ACE inhibitors due to
blockade of peptidase activity. ACE inhibitors decrease formation of angiotensin II (ANG-II) and increase kinins, N-acetyl-seryl-aspartyl-lysyl-proline
(Ac-SDKP), ANG 1–7, and other peptides that may contribute to their
antihypertensive and cardiovascular and renal protective effects. SNS, sympathetic nervous system; TxA2, thromboxane A2; PGH2, prostaglandin H2; NO,
nitric oxide; PGs, prostaglandins and prostacyclins; EDHF, endotheliumderived hyperpolarizing factor; upt, uptake; tPA, tissue plasminogen activator;
LHRH, luteinizing hormone-releasing hormone.
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(ACE) is a dipeptidyl peptidase transmembrane-bound enzyme (for review see Ref. 2). A
soluble form of ACE in plasma is derived from the plasma
membrane-bound form by proteolytic cleavage of its COOHterminal domain. There are two distinct isoforms of ACE:
somatic and testicular. They are transcribed from a single gene
at different initiation sites. The somatic form of ACE is a large
protein (150 –180 kDa) that has two identical catalytic domains
and a cytoplasmic tail. It is synthesized by the vascular endothelium and by several epithelial and neural cell types. The
testicular form of ACE is a 100- to 110-kDa protein that has a
single catalytic domain corresponding to the COOH-terminal
domain of somatic ACE and is only found in developing
spermatids and mature sperm where it may play a role in
fertilization.
ACE inhibitors have become important tools in the treatment
of hypertension, heart failure, cardiac remodeling postmyocardial infarction, and renal diseases, especially diabetic nephropathy (Table 1). Until recently, most of the biological effects of
ACE inhibitors have been attributed to inhibition of its wellcharacterized dipeptidyl peptidase activity, in particular, blockade of the conversion of angiotensin I to II and inactivation of
kinins (1). We have shown that the tetrapeptide N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP), which increases fivefold in
blood after administration of an ACE inhibitor, also participates in its anti-fibrotic and anti-inflammatory effect (12–15).
ACE hydrolyzes many other peptides, but their role in the
therapeutic or side effects of ACE inhibitors is not known
(Fig. 1).
ACE inhibitors have a number of effects that are not due to
inhibition of the peptidase activity of ACE but rather to a direct
effect on the bradykinin B2 receptor (4). Indeed, an ACE
inhibitor amplified the effects of bradykinin in vessels that
lacked measurable ACE activity (3). An ACE inhibitor also
enhanced the effect of an ACE-resistant B2 kinin receptor
agonist (3, 4). There is evidence that ACE inhibitors induced
cross-talk between the transmembrane protein ACE and the B2
kinin receptor, probably by formation of a heterodimer (10,
11). ACE inhibitors also directly activate the bradykinin B1
receptor, acting at the Zn-binding pentameric consensus sequence HEXXH (195–199) of the B1 receptor, a motif that is
present in the active center of ACE but absent from the B2
receptor (6). ACE inhibitors also induce phosphorylation of the
ACE intracellular tail (Ser1270) via CK2, resulting in outside-in
signaling that enhances expression of ACE and cyclooxygenase-2 (COX-2) (7, 8). The effect of the ACE inhibitor on
COX-2 is due to the transcription factor activator protein-1
(AP-1). This results in increased release of prostacyclin and
prostaglandin E2 by the endothelial cells that is independent of
local accumulation of kinins (7).
Editorial Focus
ACE NOVEL MECHANISM OF ACTION
challenge in the future is to determine whether these novel
effects of ACE that are not mediated by its peptidase activity
play a physiological or pathological role. In addition, it is
important to determine whether some of the therapeutic effects
of ACE inhibitors are mediated by its effects on phosphorylation of the intracellular tail of ACE and/or by cross-talk
between the bradykinin receptors and the enzyme.
GRANTS
This work was supported by National Heart, Lung, and Blood Institute
Grant HL-028982-24.
REFERENCES
1. Carretero OA, Yang XP, and Rhaleb NE. The kallikrein-kinin system
as a regulator of cardiovascular and renal function. In: Hypertension: A
Companion to Brenner and Rector’s The Kidney, edited by Oparil S and
Weber MA. Philadelphia, PA: Elsevier, 2005, p. 203–218.
2. Erdös EG. Angiotensin I converting enzyme and the changes in our
concepts through the years. Lewis K Dahl memorial lecture. Hypertension
16: 363–370, 1990.
3. Hecker M, Blaukat A, Bara AT, Müller-Esterl W, and Busse R. ACE
inhibitor potentiation of bradykinin-induced venoconstriction. Br J Pharmacol 121: 1475–1481, 1997.
AJP-Heart Circ Physiol • VOL
4. Hecker M, Pörsti I, Bara AT, and Busse R. Potentiation by ACE
inhibitors of the dilator response to bradykinin in the coronary microcirculation: interaction at the receptor level. Br J Pharmacol 111: 238 –244,
1994.
5. Ignjacev I, Kintsurashvili E, Johns C, Vitseva O, Duka A, Gavras I,
and Gavras H. Angiotensin-converting enzyme regulates bradykinin
receptor gene expression. Am J Physiol Heart Circ Physiol 289: H1814 –
H1820, 2005.
6. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, and Erdös EG.
Activation of bradykinin B1 receptor by ACE inhibitors. Int Immunopharmacol 2: 1787–1793, 2002.
7. Kohlstedt K, Busse R, and Fleming I. Signaling via the angiotensinconverting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells. Hypertension 45: 126 –132, 2005.
8. Kohlstedt K, Shoghi F, Müller-Esterl W, Busse R, and Fleming I. CK2
phosphorylates the angiotensin-converting enzyme and regulates its retention in the endothelial cell plasma membrane. Circ Res 91: 749 –756,
2002.
9. Kondoh G, Tojo H, Nakatani Y, Komazawa N, Murata C, Yamagata
K, Maeda Y, Kinoshita T, Okabe M, Taguchi R, and Takeda J.
Angiotensin-converting enzyme is a GPI-anchored protein releasing factor
crucial for fertilization. Nat Med 11: 160 –166, 2005.
10. Minshall RD, Erdös EG, and Vogel SM. Angiotensin I-converting
enzyme inhibitors potentiate bradykinin’s inotropic effects independently
of blocking its inactivation. Am J Cardiol 80: 132A–136A, 1997.
11. Minshall RD, Tan F, Nakamura F, Rabito SF, Becker RP, Marcic B,
and Erdös EG. Potentiation of the actions of bradykinin by angiotensin
I-converting enzyme inhibitors. The role of expressed human bradykinin
B2 receptors and angiotensin I-converting enzyme in CHO cells. Circ Res
81: 848 – 856, 1997.
12. Peng H, Carretero OA, Raij L, Yang F, Kapke A, and Rhaleb NE.
Antifibrotic effects of N-acetyl-seryl-aspartyl-lysyl-proline on the heart
and kidney in aldosterone-salt hypertensive rats. Hypertension 37: 794 –
800, 2001.
13. Peng H, Carretero OA, Vuljaj N, Liao T-D, Motivala A, Peterson EL,
and Rhaleb N-E. Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation. In press.
14. Rasoul S, Carretero OA, Peng H, Cavasin MA, Zhuo J, SanchezMendoza A, Brigstock DR, and Rhaleb N-E. Antifibrotic effect of
Ac-SDKP and angiotensin-converting enzyme inhibition in hypertension.
J Hypertens 22: 593– 603, 2004.
15. Rhaleb N-E, Peng H, Yang X-P, Liu Y-H, Mehta D, Ezan E, and
Carretero OA. Long-term effect of N-acetyl-seryl-aspartyl-lysyl-proline
on left ventricular collagen deposition in rats with 2-kidney, 1-clip hypertension. Circulation 103: 3136 –3141, 2001.
289 • NOVEMBER 2005 •
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Fig. 2. Novel mechanisms of ACE (left) and ACE inhibitors (right) that are
not mediated by either ACE dipeptidase activity or inhibition of their catalytic
sites.
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