Angiotensin I-Converting Enzyme Modulates Neutral Endopeptidase Activity in the Rat

Abstract

Abstract-Angiotensin I is a substrate for both ACE and for neutral endopeptidase 24.11 (NEP). We hypothesized that high ACE expression is related to low NEP activity. Accordingly, circulating and tissue NEP and ACE activities were measured by fluorometry in homozygous rats (F 0 and F 2 ) for the Lewis microsatellite allele (LL, low ACE) and for the Brown Norway microsatellite allele (BB, high ACE). Plasma, lung, and aortic ACE activities in F 0 and F 2 were higher in BB rats than in LL rats (PϽ0.01), whereas left ventricular ACE activity was similar in both genotypes. In contrast, NEP activity in the LL group was higher in the serum, aorta, and lungs in F 0 and F 2 homozygous (PϽ0.05 Key Words: angiotensin-converting enzyme Ⅲ angiotensin Ⅲ polymorphism Ⅲ neutral endopeptidase A ngiotensin I-converting enzyme plays an important role in the regulation of the renin angiotensin system (RAS) by hydrolyzing angiotensin (Ang) I to Ang II and degrading bradykinin to bradykinin-(1-7) and Ang-(1-7) to Ang-(1-5), both inactive peptides. In this way, ACE activity influences circulating and tissue levels of Ang II, contributes to regulate the vasculature tone, and may have some effects on cardiac and vascular mass and structure. 1 Neutral endopeptidase (NEP, enkephalinase, neprilysin, EC 3.4.24.11) is a transmembrane zinc metalloendopeptidase, present at the surface of several tissues. 2 NEP also participates in the RAS, cleaving Ang I and Ang II. 3,4 The action of NEP on Ang I generates Ang-(1-7), an heptapeptide with vasodilator activity. The physiological effects of Ang-(1-7) are opposite those of Ang II and would favor a blood pressure-lowering effect under conditions of high Ang II activity. 3,4 In humans, the ACE gene insertion/deletion (I/D) polymorphism is due to the presence (insertion) or absence (deletion) of a 287-bp sequence in the intron 16 on the chromosome 17q23 5 and determines plasma ACE levels by 50%. The D allele is associated with increased ACE and possibly increased Ang II levels. 6,7 Recent evidence suggests that the DD genotype-with higher plasma ACE activity-is associated with higher risk of hypertension in men. 8 A similar polymorphism has been observed in normotensive rats, whereas homozygous rats for the Lou and Lewis microsatellite alleles have lower ACE activity than that of homozygous rats for the Brown Norway microsatellite allele (BB). 9 It remains unknown whether NEP activity-because of its interaction with Ang I and Ang II as well as with bradykinin-is modulated by ACE expression. Because higher ACE activity will decrease Ang I and bradykinin levels and increase Ang II levels, we hypothesized that an inverse relationship between ACE expression (genetically determined) and NEP activity might exist. To test this hypothesis, NEP activity was determined in serum and in different tissues from male Lewis homozygous (LL, genetically with low ACE activity) and BB rats (genetically with high ACE activity) in F 0 and in homozygous F 2. These rats were also characterized by their ACE genotype and circ...

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

“…[7][8][9] Recently, we demonstrated in normotensive rats the influence of an ACE gene polymorphism on different levels of circulating and tissue NEP activities, suggesting the existence of a modulatory effect of ACE expression on NEP activity in the rat. 34 NEP activity was significantly decreased in serum and tissues in rats with genetically high ACE activity, with an inverse relationship between NEP and ACE activities. 34 The inverse relationship between plasma ACE and plasma NEP activity observed here in normotensive human subjects is consistent with the previous experimental observation in rats.…”

“…34 NEP activity was significantly decreased in serum and tissues in rats with genetically high ACE activity, with an inverse relationship between NEP and ACE activities. 34 The inverse relationship between plasma ACE and plasma NEP activity observed here in normotensive human subjects is consistent with the previous experimental observation in rats. In humans, the D ACE allele has been associated with cardiovascular disease, which may be related to enhanced Ang-II production and/or to degradation of BK.…”

La sobreexpresión del gen de enzima convertidora de angiotensina homóloga (ECA2) revierte la hipertensión arterial y el remodelado cardíaco experimental

“…Además, la sobreexpresión de ECA2 regresó la fibrosis cardíaca en el modelo de HTA dependiente de Ang II, siendo la regresión de la fibrosis cardíaca mayor en las ratas LL AdECA2 respecto de las ratas BN. El modelo de ratas homocigotas LL y BN ha sido ampliamente utilizado en investigaciones previas del laboratorio 14,15,16 describiendo que en condiciones basales, las ratas BN presentan mayores niveles de ECA, renina y Ang II pero baja actividad de NEP y Ang-(1-7) 13,14 . En cambio, las ratas LL presentan características opuestas.…”

Increased Aortic NADPH Oxidase Activity in Rats With Genetically High Angiotensin-Converting Enzyme Levels

“…Normotensive strains of male rats (7 weeks of age), homozygous F 2 LL (nϭ25), and BB strains (nϭ36), with contrasting levels of plasma ACE, were used. 13,15,16 The F 2 homozygous strains were obtained after mating male F 0 BB with female LL inbreed strains obtained from Charles River (Wilmington, Mass). These F 0 rats produced F 1 hybrids that were mated to obtain the F 2 cohort.…”

“…8,9 Previous identification of a microsatellite marker in the rat ACE gene, specifically in the intron 13 on chromosome 10, has also allowed differentiation of ACE polymorphism alleles among different rat strains 10,11 and their association with different levels of plasma ACE 12 and neutral endopeptidase. 13,14 This genetically determined ACE expression in rats enhances the chronic hypertensive response after the induction of renovascular hypertension. 15 In addition, a relationship between circulating Ang II and the development of hypertension was also observed in this experimental model of genetically modulated hypertension.…”