Angiotensin I-Converting Enzyme Genotype Influences Arterial Response to Injury in Normotensive Rats

Abstract

Abstract-Two normotensive strains of rat, the Lou and Brown Norway (BN) strains, have contrasting levels of plasma angiotensin-converting enzyme (ACE). To investigate the degree of genetic determination of ACE expression, a polymorphic marker of the ACE gene was analyzed in inbred rats of the two strains. The two inbred strains were shown to bear different alleles for a polymorphic marker at the ACE gene. The segregation of the alleles of this marker and the plasma ACE levels were studied in a group of F2 rats issued from a cross between Lou and BN rats. The degree of genetic determination of plasma ACE activity was estimated to be 94% in the F2 cohort. The ACE locus accounts for 74% of total plasma ACE variance. ACE activity and mRNA expression in lungs were also genetically determined. The difference observed in ACE mRNA accumulation in the lungs between the two strains was due to a difference in the transcriptional rate of the ACE gene, as shown in nuclear run-on experiments. No differences were observed in arterial blood pressure of homozygous F2 progeny. In these animals, ACE genotype did not interfere with the pressor or the depressor responses to ACE-dependent vasoactive peptides. There was a significant effect of strain on constitutive or inducible membrane or soluble ACE activity in primary cultures of vascular cells. Neointima formation in the carotid artery 14 days after balloon injury was also influenced by the genotype in F2 homozygous progeny, whereas the medial area was not. These results demonstrate that there is a close relationship between the genetically determined ACE expression and the inducibility of the ACE gene. The degree of genetic determination of ACE expression in inbred rat strains offers a unique opportunity to study the interaction between genetic and environmental determinants of ACE expression and its involvement in response to experimental cardiovascular and renal injury. (Arterioscler Thromb Vasc Biol. 1998;18:235-243.)

Differential ACE expression among tissues in allele-specific Wistar rat lines

“…Animal models would be helpful to unravel these complex interactions in well-controlled experimental conditions. Therefore, we investigated the previously described difference between the B and L alleles (between the Brown Norway and Lou rats) (Challah et al 1998) and identified these alleles in the outbred Wistar rat. We bred two lines homozygous for the two alleles (called WU-B and WU-L) and determined their phenotype related to ACE in serum, heart, and kidney tissue.…”

“…These measurements showed clearly that both the ACE activity and mRNA expression were related to the B and L alleles and suggested that ACE activity is controlled at the transcriptional level. Challah et al (1998) …”

“…The ACE locus determines 74% of the plasma ACE activity in Brown Norway (B allele) and Lou (L allele) rats after cross-breeding, where the B allele is related to high ACE activity and the L allele to low ACE activity (Challah et al 1998;Hilbert et al 1991). Challah et al (1998) demonstrated that ACE activity in cultured vascular cells and in neointima formation in the carotid artery after balloon injury was influenced by ACE levels.…”

“…The ACE locus determines 74% of the plasma ACE activity in Brown Norway (B allele) and Lou (L allele) rats after cross-breeding, where the B allele is related to high ACE activity and the L allele to low ACE activity (Challah et al 1998;Hilbert et al 1991). Challah et al (1998) demonstrated that ACE activity in cultured vascular cells and in neointima formation in the carotid artery after balloon injury was influenced by ACE levels. Moreover, Ocaranza et al (2002Ocaranza et al ( , 2004 showed that there is an enhanced hypertensive response and more fibrosis in response to myocardial infarction in the Brown Norway rat with higher ACE levels.…”

Système rénine-angiotensine et remodelage vasculaire

“…De façon analogue, les inhibiteurs du système rénine-angiotensine diminuent la prolifération intimale des cellules musculaires lisses secondaire à une angioplastie. Par ailleurs, le polymorphisme d'expression de l'enzyme de conversion influence le taux de resténose après angioplastie chez l'animal [28] comme chez l'homme [29]. Ces effets sont essentiellement dus à l'angiotensine II interstitielle, produite localement, au niveau des cellules musculaires lisses ou des fibroblastes, à partir de la rénine et de l'angiotensinogène adsorbés dans les tissus.…”