Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction contribute to the development of coronary heart disease. In a study comparing patients after myocardial infarction with controls, we have explored a possible association between coronary heart disease and a variation found in the gene encoding angiotensin-converting enzyme (ACE). The polymorphism ACE/ID is strongly associated with the level of circulating enzyme. This enzyme plays a key role in the production of angiotensin II and in the catabolism of bradykinin, two peptides involved in the modulation of vascular tone and in the proliferation of smooth muscle cells. Here we report that the DD genotype, which is associated with higher levels of circulating ACE than the ID and II genotypes, is significantly more frequent in patients with myocardial infarction (n = 610) than in controls (n = 733) (P = 0.007), especially among subjects with low body-mass index and low plasma levels of ApoB (P < 0.0001). The ACE/ID polymorphism seems to be a potent risk factor of coronary heart disease in subjects formerly considered to be at low risk according to common criteria.

Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction.

Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

Physiology of local renin-angiotensin systems.

Pcr detection of the insertion/ deletion polymorphism of the human angiotensin converting enzyme gene

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

The hypothesis of a genetic control of plasma angiotensin I-converting enzyme (ACE) level has been suggested both by segregation analysis and by the identification of an insertion/deletion (I/D) polymorphism of the ACE gene, a polymorphism contributing much to the variability of ACE level. To elucidate whether the I/D polymorphism was directly involved in the genetic regulation, plasma ACE activity and genotype for the I/D polymorphism were both measured in a sample of 98 healthy nuclear families. The pattern of familial correlations of ACE level was compatible with a zero correlation between spouses and equal parent-offspring and sib-sib correlations (.24 +/- .04). A segregation analysis indicated that this familial resemblance could be entirely explained by the transmission of a codominant major gene. The I/D polymorphism was associated with marked differences of ACE levels, although these differences were less pronounced than those observed in the segregation analysis. After adjustment for the polymorphism effects, the residual heritability (.280 +/- .096) was significant. Finally, a combined segregation and linkage analysis provided evidence that the major-gene effect was due to a variant of the ACE gene, in strong linkage disequilibrium with the I/D polymorphism. The marker allele I appeared always associated with the major-gene allele s characterized by lower ACE levels. The frequency of allele I was .431 +/- .025, and that of major allele s was .557 +/- .041. The major gene had codominant effects equal to 1.3 residual SDs and accounted for 44% of the total variability of ACE level, as compared with 28% for the I/D polymorphism.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.

A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.

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An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

The expression of angiotensin-I converting enzyme (ACE; EC 3.4.15.1) in human circulating mononuclear cells was studied. T-lymphocytes contained the highest level of enzyme, approx. 28 times more per cell than monocytes. No activity was detected in B-lymphocytes. ACE was present mainly in the microsomal fraction, where it was found to be the major membrane-bound bradykinin-inactivating enzyme. An mRNA for ACE was detected and characterized after reverse transcription and amplification by PCR in T-lymphocytes and several T-cell leukaemia cell lines. We have previously observed that the interindividual variability in the levels of ACE in plasma is, in part, genetically determined and influenced by an insertion/deletion polymorphism of the ACE gene. To investigate the mechanisms involved in the regulation of ACE biosynthesis, the ACE levels of T-lymphocytes from 35 healthy subjects having different ACE genotypes were studied. These levels varied widely between individuals but were highly reproducible and influenced by the polymorphism of the ACE gene. T-lymphocyte levels of ACE were significantly higher in subjects who were homozygote for the deletion than in the other subjects. These results show that ACE is expressed in T-lymphocytes and indicate that the level of ACE expression in cells synthesizing the enzyme is genetically determined.

/pdf/angiotensin-i-converting-enzyme-in-human-circulating-4sgmbxu8wp.pdf

Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes.

The two homologous domains of human angiotensin I-converting enzyme are both catalytically active.

The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors.

Expression and characterization of recombinant human angiotensin I-converting enzyme. Evidence for a C-terminal transmembrane anchor and for a proteolytic processing of the secreted recombinant and plasma enzymes

F. Alhenc-Gelas

Papers

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes.

The two homologous domains of human angiotensin I-converting enzyme are both catalytically active.

The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors.

Expression and characterization of recombinant human angiotensin I-converting enzyme. Evidence for a C-terminal transmembrane anchor and for a proteolytic processing of the secreted recombinant and plasma enzymes