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Am J Physiol Heart Circ Physiol 286: H498-H506, 2004. First published October 2, 2003; doi:10.1152/ajpheart.00102.2003
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Polymorphism in gene coding for ACE determines different development of myocardial fibrosis in rats

María Paz Ocaranza,1,2 Guillermo Díaz-Araya,3 Juan E. Carreño,1 David Muñoz,1 Juan Pablo Riveros,1 Jorge E. Jalil,1 and Sergio Lavandero2,4,5

1Departamento Enfermedades Cardiovasculares, Escuela de Medicina, P. Universidad Católica de Chile, and Departamentos de 2Bioquímica and Biología Molecular; 3Química Farmacológica y Toxicológica, Facultad Ciencias Químicas y Farmacéuticas; 4Programa Biología Celular y Molecular, Instituto Ciencias Biomédicas, Facultad de Medicina; and 5Centro Estudios Moleculares de la Célula, Universidad de Chile, Olivos 1007, Santiago 6640750, Chile

Submitted 3 February 2003 ; accepted in final form 25 September 2003

In humans, the effect of angiotensin-converting enzyme (ACE) gene polymorphisms in cardiovascular disease is still controversial. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE gene polymorphism among strains with different ACE levels. We tested the hypothesis that this ACE gene polymorphism determines the extent of cardiac fibrosis induced by isoproterenol (Iso) in the rat. We used a male F2 generation (homozygous LL and BB ACE genotypes determined by polymerase chain reaction) derived from two rat strains [Brown-Norway (BB) and Lewis (LL)] that differ with respect to their plasma ACE activities. For induction of left ventricular (LV) hypertrophy (LVH) and cardiac fibrosis, rats were infused with Iso (5 mg·kg–1·day–1) or saline (control) for 10 days and euthanized at day 1 after the last injection. The interstitial collagen volumetric fraction (ICVF), collagen I, and fibronectin content, but not collagen III content, were significantly higher in the homozygous BB rats than in homozygous LL rats. Differences in metalloprotease (MMP)-9, but not in MMP-2 activities as well as in cardiac cell proliferation, were also detected between LL and BB rats treated with Iso. LV ACE activity was higher in BB rats than LL rats and correlated with ICVF (r = 0.61, P < 0.002). No changes were observed in plasma ACE activities, ANG II plasma or LV levels, plasma renin activity, and ACE and ANG II type 1 receptor (AT1R) mRNA levels in the LV of rats with the two different ACE polymorphisms. Iso induced a similar degree of LVH [assessed by an increase in LV weight 100 per body weight, LV-to-right ventricle (RV) ratio, and LV protein content] in LL and BB rats. We concluded that rats in the F2 generation with high plasma ACE activity developed more fibrosis but to a similar degree of LVH compared with rats with low plasma ACE activity.

renin angiotensin system; fibrosis; hypertrophy; angiotensin-converting enzyme; angiotensin-converting enzyme gene polymorphism


Address for reprint requests and other correspondence: S. Lavandero, Dept. Biochemistry & Molecular Biology, Faculty Chemical & Pharmaceutical Sciences & Fondap Center for Molecular Studies of the Cell, University of Chile, Olivos 1007, Santiago 6640750, Chile (E-mail: slavander{at}uchile.cl). J. E. Jalil, Dept. of Cardiovascular Diseases, School of Medicine, P. Catholic University of Chile, Marcoleta 345, Santiago, Chile (E-mail: jjalil{at}med.puc.cl).




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