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

From INSERM unités 460 (M.C., M.P., J.-B.M.), 358 (E.V., F.S.), and 153 (A.R.-D.), Paris; Departement de Biostatistique et Informatique Medicale, Paris (B.G.); and Institut de Recherches Servier, Suresnes (P.J., J.-P.V.), France.

Correspondence to Jean-Baptiste Michel, INSERM U460, Remodelage CardioVasculaire, UFR de Médecine X. Bichat, 16, rue Henri Huchard, 75870 Paris Cedex 18, France.

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.

Key Words: angioplasty • angiotensin • cells • gene • genetic

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