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Angiotensin II binding and extracellular matrix remodelling in a rat model of myocardial infarction

Department of Human Morphology, Faculty of Medicine, American University of Beirut

Khaled A Hassan

Department of Physiology, American University of Beirut

Adel E Birbari

Department of Physiology, American University of Beirut

Khalil M Bitar

Department of Physics, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon

Anwar B Bikhazi

Department of Physiology, American University of Beirut, ab04@ aub.lb.edu

Clinical evidence points to a role for angiotensin II (Ang II) in the post-infarction remodelling of cardiac hypertrophy. The present study was designed to investigate the remodelling process in an animal model of myocardial infarction (MI) using the following criteria: 1) histological studies to examine the re-vascularisation process and collagen deposition in different regions of the myocardium; 2) histological evidence to investigate the cell type distribution using cell-specific markers; 3) histological and Western blot analysis to localise Ang II receptor subtypes (AT₁-receptor and AT₂-receptor) and to study their regulation; 4) kinetics of the binding of Ang II to its receptors in a heart perfusion model; and 5) to assess the effect of the Ang II antagonist (losartan) on these parameters.

MI was induced by ligation of the left anterior descending coronary artery of Sprague-Dawley rats. Four different animal groups were established: 1) sham-operated, non-treated; 2) sham-operated, treated with losartan; 3) myocardial infarct, non-treated; and

4) myocardial infarct, treated with losartan. In infarcted rat hearts, fibroblasts and collagen types I and III increased in the remnant viable region of the left ventricle compared with sham-operated rats. One month of losartan treatment in myocardial infarcted rats revealed insignificant changes in fibroblasts and collagen types I and III compared with sham controls. Also, myocardial infarction increased AT₁-receptor protein levels compared with sham-operated controls, as judged by Western blotting. In losartan-treated myocardial infarct animals, no changes were detected at the level of AT₁-receptor expression compared with non-treated myocardial infarct rats. Binding studies of Ang II on endothelial cell lining and directly on myocytes in sham-operated and infarcted perfused rat hearts revealed that, in myocardial infarcted-animals, Ang II binding affinity increased both in the endothelium and in myofibres. This may be considered a major putative effect of the peptide in potentiating the pharmacodynamics of hypertrophy. In losartan-treated myocardial infarcted-animals, a marked increase in the binding affinities of Ang II for the AT₂-receptor subtype was observed. Hence, potential cardioprotective effects of the AT ₁-receptor antagonist are proposed.

Key Words: angiotensin • myocardial infarction • remodelling • losartan

Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 4, 369-378 (2000)
DOI: 10.3317/jraas.2000.069


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