Associate Editor: C.M. Villalón
ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition?

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Abstract

Angiotensin (Ang)-converting enzyme (ACE) inhibitors are widely used for the treatment of cardiovascular diseases. Not all patients respond to ACE inhibitors, and it has been suggested that genetic variation might be a useful marker to predict the therapeutic efficacy of these drugs. In particular, the ACE insertion (I)/deletion (D) polymorphism has been investigated in this regard. Despite a decade of intensive research involving the genotyping of thousands of patients, we still do not know whether ACE genotyping helps in predicting the success of ACE inhibition. This review critically addresses the concept that predictive information on therapeutic efficacy of ACE inhibitors might be obtained based on ACE genotyping. It answers the following questions: Do higher ACE levels really result in higher Ang II levels? Is ACE the only converting enzyme in humans? Does ACE inhibition affect ACE expression? Why does ACE have 2 catalytically active domains? What is the relevance of ACE inhibitor-induced signaling through membrane-bound ACE? The review ends with the proposal that ACE phenotyping may prove to be a better first step toward personalized medicine for ACE inhibitors than ACE genotyping.

Introduction

Angiotensin (Ang)-converting enzyme (ACE) inhibitors are widely used for the treatment of cardiovascular diseases. However, their mechanism of action is not completely understood. In general, it is believed that these drugs block Ang II generation at tissue sites rather than Ang II generation in circulating blood (Dzau, 1988, van den Meiracker et al., 1992, Campbell et al., 1994, van Kats et al., 2000, van Kats et al., 2005). In addition, interference with the metabolism of ACE substrates other than Ang I (e.g., bradykinin and N-acetyl-Ser-Asp-Lys-Pro) may contribute to their beneficial effects (Gainer et al., 1998, Azizi et al., 2002, Peng et al., 2005).

Not all patients respond to ACE inhibitors (Dickerson et al., 1999, Struthers et al., 2001), and it has been suggested that genetic variation might be a useful marker to predict the therapeutic efficacy of these drugs (Turner et al., 2001). In particular, the ACE insertion (I)/deletion (D) polymorphism has been investigated in this regard, although no conclusive data have been obtained. This polymorphism, corresponding with a 287-base pair insert in intron 16 of the gene, associates with the ACE concentration in blood and tissues, subjects with 1 or 2 D alleles having approximately 30% and 60% higher ACE levels, respectively, than subjects with the II genotype (Rigat et al., 1990). Subjects with the DD genotype are assumed to display increased Ang II generation and require higher doses of ACE inhibitors to fully suppress ACE.

This review critically addresses the idea that predictive information on therapeutic efficacy of ACE inhibitors can be obtained based on ACE genotyping. It will also answer the following questions: Do higher ACE levels really result in higher Ang II levels? Is ACE the only converting enzyme in humans? Does ACE inhibition affect ACE expression? Why does ACE have 2 catalytically active domains? What is the relevance of ACE inhibitor-induced signaling through membrane-bound ACE? The review ends with the proposal that ACE phenotyping may prove to be a better first step toward personalized medicine for ACE inhibitors than ACE genotyping. Moreover, given the equieffectiveness of ACE inhibitors and Ang II type 1 (AT1) receptor blockers, such phenotyping might also be of use to determine the response to AT1 receptor blockers.

Section snippets

ACE variation and Ang II generation

Ang II generation depends on renin, angiotensinogen, and ACE. Renin cleaves angiotensinogen to generate Ang I, and Ang I is subsequently converted to Ang II by ACE. The renin–Ang system is a feedback-regulated system, and compensatory mechanisms will rapidly neutralize alterations of one of the components. For instance, Ang II inhibits renin release; thus, a rise in Ang II will immediately be counteracted by a reduction in renin release.

Circulating ACE levels, although stable within 1 healthy

Role of alternative Ang II-generating enzymes

In vitro studies, often making use of homogenized tissue, suggest that ACE is not the only enzyme capable of generating Ang II. First, there are enzymes cleaving Ang II directly from angiotensinogen, such as tonin (Grise et al., 1981). However, the lack of Ang II in hearts of nephrectomized animals, which contain high levels of angiotensinogen (Campbell et al., 1993, Danser et al., 1994, Nussberger, 2000), strongly argues against an in vivo role of such enzymes. Second, in vitro studies in

ACE upregulation following ACE inhibition?

ACE inhibition acutely results in renin release from the kidney because it no longer allows Ang II to suppress renin release via AT1 receptor activation. As a consequence, Ang I generation will increase (Mooser et al., 1990); thus, depending on the degree of ACE inhibition, Ang II levels will rise again, sometimes to levels above baseline (Campbell et al., 1993, Campbell et al., 1995, van Kats et al., 2000). For instance, at 90% ACE inhibition, a 10-fold rise in renin is sufficient to fully

ACE C-domain versus N-domain

Humans express 2 ACE isoforms, namely somatic ACE and testis ACE. Somatic ACE is abundantly present throughout the body, whereas testis ACE is found exclusively in the testis. The beneficial effects of ACE inhibitors are due to blockade of somatic ACE.

Somatic ACE has 2 homologous domains, each containing an active center. The 2 domains have 60% sequence identity. According to their positions (N-terminal and C-terminal), the domains are designated as N-domain and C-domain, respectively. Testis

ACE inhibitor-induced signaling

ACE inhibitors have been reported to potentiate bradykinin beyond blocking its hydrolysis, either by inducing ACE-bradykinin type 2 (B2) receptor ‘cross-talk’ (Minshall et al., 1997, Benzing et al., 1999) or via a direct stimulation of bradykinin type 1 (B1) receptors (Ignjatovic et al., 2002). The former claim was based on the use of bradykinin analogues, which were wrongly assumed to be ACE resistant (Dendorfer et al., 2001, Gobeil et al., 2002) and subsequent studies with truly ACE-resistant

ACE I/D polymorphism and the response to ACE inhibition

Many studies have been performed to address the possibility that ACE I/D genotyping helps in predicting the efficacy of ACE inhibition without predefining what to expect. In this respect, (i) will D allele carriers respond less well to ACE inhibition because they are, by definition, due to their higher ACE levels — underdosed (i.e., there is a pharmacokinetic difference)? or (ii) will they respond more strongly because their condition at the start of therapy is worse due to the many deleterious

Conclusions: ACE phenotyping instead of genotyping?

To explain the lack of success of ACE I/D genotyping, several aspects need to be considered. First, the ACE I/D polymorphism is just 1 of > 160 polymorphisms at the ACE locus, many of which are not in linkage disequilibrium with the ACE I/D polymorphism (Rieder et al., 1999, Sayed-Tabatabaei et al., 2006); it explains < 20% of the total ACE variability. Therefore, it seems unlikely that, at standard ACE inhibitor doses, significant underdosing will occur in DD subjects. Second, the 30–60% rise in

References (137)

  • P.K. Jacobsen et al.

    Time to consider ACE insertion/deletion genotypes and individual renoprotective treatment in diabetic nephropathy?

    Kidney Int

    (2006)
  • E. Jaspard et al.

    Catalytic properties of the two active sites of angiotensin I-converting enzyme on the cell surface

    Biochem Biophys Res Commun

    (1995)
  • M. Kohno et al.

    Association between angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in patients treated with angiotensin-converting enzyme inhibitors

    Am J Med

    (1999)
  • D.M. McNamara et al.

    Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure

    J Am Coll Cardiol

    (2004)
  • M. Miyazaki et al.

    Pathological roles of angiotensin II produced by mast cell chymase and the effects of chymase inhibition in animal models

    Pharmacol Ther

    (2006)
  • S. Mizuiri et al.

    Angiotensin-converting enzyme (ACE) I/D genotype and renal ACE gene expression

    Kidney Int

    (2001)
  • U.F. Mondorf et al.

    Contribution of angiotensin I converting enzyme gene polymorphism and angiotensinogen gene polymorphism to blood pressure regulation in essential hypertension

    Am J Hypertens

    (1998)
  • Y. Nakano et al.

    Angiotensin I-converting enzyme gene polymorphism and acute response to captopril in essential hypertension

    Am J Hypertens

    (1997)
  • N. Ohmichi et al.

    Relationship between the response to the angiotensin converting enzyme inhibitor imidapril and the angiotensin converting enzyme genotype

    Am J Hypertens

    (1997)
  • R.B. Perich et al.

    Structural constraints of inhibitors for binding at two active sites on somatic angiotensin converting enzyme

    Eur J Pharmacol

    (1994)
  • A. Perna et al.

    ACE genotype and ACE inhibitors induced renoprotection in chronic proteinuric nephropathies1

    Kidney Int

    (2000)
  • F. Ribichini et al.

    Cellular immunostaining of angiotensin-converting enzyme in human coronary atherosclerotic plaques

    J Am Coll Cardiol

    (2006)
  • P. Ruggenenti et al.

    Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury

    Am J Kidney Dis

    (2000)
  • M.A.D.H. Schalekamp et al.

    Angiotensin II production and distribution in the kidney: I. A kinetic model

    Kidney Int

    (2006)
  • M.A.D.H. Schalekamp et al.

    Angiotensin II production and distribution in the kidney: II. Model-based analysis of experimental data

    Kidney Int

    (2006)
  • P.J.J. Admiraal et al.

    Regional angiotensin II production in essential hypertension and renal artery stenosis

    Hypertension

    (1993)
  • T. Alexiou et al.

    Angiotensinogen and angiotensin-converting enzyme gene copy number and angiotensin and bradykinin peptide levels in mice

    J Hypertens

    (2005)
  • F. Alhenc-Gelas et al.

    Distribution of plasma angiotensin I-converting enzyme levels in healthy men: relationship to environmental and hormonal parameters

    J Lab Clin Med

    (1991)
  • D.K. Arnett et al.

    Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study

    Circulation

    (2005)
  • M. Azizi et al.

    Functional consequences of angiotensin-converting enzyme gene polymorphism on N-acetyl-Ser-Asp-Lys-Pro degradation and angiotensin II production

    J Mol Med

    (2002)
  • I.V. Balyasnikova et al.

    Localization of an N-domain region of angiotensin-converting enzyme involved in the regulation of ectodomain shedding using monoclonal antibodies

    J Proteome Res

    (2005)
  • T. Benzing et al.

    Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells

    Circulation

    (1999)
  • L.J. Bloem et al.

    Racial difference in the relationship of an angiotensin I-converting enzyme gene polymorphism to serum angiotensin I-converting enzyme activity

    Hypertension

    (1996)
  • F. Boomsma et al.

    Opposite effects of captopril on angiotensin I-converting enzyme ‘activity’ and ‘concentration’; relation between enzyme inhibition and long-term blood pressure response

    Clin Sci (Lond)

    (1981)
  • D.J. Campbell et al.

    Nephrectomy, converting enzyme inhibition, and angiotensin peptides

    Hypertension

    (1993)
  • D.J. Campbell et al.

    Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides

    Hypertension

    (1994)
  • D.J. Campbell et al.

    Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme

    J Cardiovasc Pharmacol

    (1995)
  • D.J. Campbell et al.

    Effect of reduced angiotensin-converting enzyme gene expression and angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptide levels in mice

    Hypertension

    (2004)
  • S.M. Danilov et al.

    Development of enzyme-linked immunoassays for human angiotensin I converting enzyme suitable for large-scale studies

    J Hypertens

    (1996)
  • S.M. Danilov et al.

    ACE phenotyping as a guidance towards personalized medicine with ACE inhibitors

    J Hypertens

    (2006)
  • A.H.J. Danser et al.

    Metabolism of angiotensin I by different tissues in the intact animal

    Am J Physiol

    (1992)
  • A.H.J. Danser et al.

    Production of angiotensins I and II at tissue sites in intact pigs

    Am J Physiol

    (1992)
  • A.H.J. Danser et al.

    Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis

    Hypertension

    (1994)
  • A.H.J. Danser et al.

    Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism

    Circulation

    (1995)
  • A.H.J. Danser et al.

    Angiotensinogen (M235T) and angiotensin-converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels

    J Hypertens

    (1998)
  • A.H.J. Danser et al.

    Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans

    J Hypertens

    (1998)
  • A.H.J. Danser et al.

    Angiotensin I to angiotensin II conversion in the human forearm and leg. Effect of the angiotensin converting enzyme gene insertion/deletion polymorphism

    J Hypertens

    (1999)
  • L.M. de Lannoy et al.

    Angiotensin-converting enzyme is the main contributor to angiotensin I–II conversion in the interstitium of isolated perfused rat heart

    J Hypertens

    (2001)
  • A. Dendorfer et al.

    Potentiation of kinin analogues by ramiprilat is exclusively related to their degradation

    Hypertension

    (2001)
  • A. Dendorfer et al.

    Potentiation of the vascular response to kinins by inhibition of myocardial kininases

    Hypertension

    (2000)
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