Neutral endopeptidase and angiotensin I converting enzyme insertion/deletion gene polymorphism in humans

Abstract

Neutral endopeptidase (NEP) hydrolyses angiotensins (Ang) I and II and generates angiotensin-(1-7) ]. In humans, the insertion/deletion (I/D) angiotensin-I converting enzyme (ACE) gene polymorphism determined plasma ACE levels by 40%. In rats, a similar polymorphism determines ACE levels which are inversely associated to NEP activity. The objective of this study is to evaluate the relationship between ACE expression and plasma NEP activity in normotensive subjects and in hypertensive patients. In total, 58 consecutive patients with hypertension, evaluated in our Hypertension Clinic, were compared according to their ACE I/D genotypes with 54 control subjects in terms of both plasma ACE activity and NEP activities. Plasma ACE activity was elevated 51 and 70% in both DD ACE groups (normotensives and hypertensives) compared with their respective ID and II ACE groups (Po0.001). A significant effect of the ACE polymorphism and of the hypertensive status on ACE activity was observed (Po0.001). In normotensive DD ACE subjects, NEP activity was 0.30 7 0.02 U/ml, whereas in the normotensive II ACE and in the normotensive ID ACE subjects NEP activity was increased 65 and 48%, respectively (Po0.001). In the hypertensive DD ACE patients, NEP activity was 0.47 7 0.03 U/mg. An effect of the I/D ACE genotypes on NEP activity (Po0.04) and an interaction effect between the I/D ACE genotype and the hypertensive status were also observed (Po0.001). These results are consistent with a normal and inverse relationship between the ACE polymorphism and NEP activity in normotensive humans (as is also observed in rats). This normal relationship is not observed in hypertensive patients.

Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1–7) in regulation of cardiovascular function

“…Surgical correction of the stenotic kidney was associated with normalization of plasma levels of both ANG II and ANG-(1-7). Indirect evidence for a potential deficit in ANG-(1-7) production was obtained by Jalil et al (59) who reported a loss of the inverse relationship between ACE polymorphism and plasma neprilysin activity in essential hypertensive subjects. In addition, lower levels of plasma ANG-(1-7) in preeclamptic subjects (74) contrasted with a progressive rise of ANG-(1-7) throughout gestation (106).…”

Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid β-protein metabolism in mouse models of Alzheimer disease

“…It was apparent that the prolonged captopril administration was effective at maintaining ACE inhibition in the kidney (Fig 3B), but not in the brain (Fig 3A) even at the high dose used, possibly due to the relatively low level of brain penetration and the high variability in ACE activity within this cohort of mice. Previous studies suggest that there may be a compensatory genetic co-regulation of ACE and NEP levels (Jalil et al, 2004;Jongun, 2004), such that low ACE activity may stimulate NEP expression. To exclude NEP upregulation as the cause of the observed preservation of Aβ levels between treatment groups, we tested NEP activity in kidney and brain tissue (Fig 3B) and found no difference between treatment groups.…”

Effect of hypertension on angiotensin-(1–7) levels in rats with different angiotensin-I converting enzyme polymorphism

“…In the aforementioned experiments, plasma ACE activity was inversely correlated with serum and lung NEP activities (aortic ACE and NEP activities were also inversely correlated) (Oliveri et al, 2001). Thus, genetically determined higher ACE expression in ratsas well as in humans-is inversely related to NEP activity, which probably will be also associated with lower Ang-(1 -7) tissue levels (and vice versa) (Oliveri et al, 2001;Jalil et al, 2004). There are no data on the role of ACE2 in determining Ang-(1 -7) levels in these rats with genetically determined ACE expression.…”