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