Since the first observation by Spann et al., it has become clear that in cardiac hypertrophy induced by a mechanical overloading, the velocity of shortening of the cardiac muscle (Vmax) is reduced (see ref. 2 for review). Most authors agree that this mechanical alteration is accompanied by a decrease in the Ca2+-dependent ATPase activity of myosin (see ref. 3 for review). The molecular basis of such changes was unknown because the structural modifications of the myosin molecule were ill-defined. Nevertheless, it has recently been shown that, like skeletal muscle myosin, cardiac myosin is composed of several polymorphic forms, comparable to isoenzymes. In the skeletal muscle, new functional requirements can induce changes in both contractile activity and type of myosin isoenzyme synthesised. We now report that an increase in cardiac work produced by mechanical overloading in rats induces the preferential synthesis of a cardiac myosin isoenzyme characterised by specific immunological and electrophoretic properties and exhibiting a lower ATPase activity. This adaptive change could account for the reduced shortening speed of this hypertrophied cardiac muscle.

Cardiac fibrosis is one of the deleterious events accompanying hypertension that may be implicated in the progression toward heart failure. To determine the mechanisms involved in fibrosis and the role of hemodynamic versus humoral factors, we studied the expression of genes involved in hypertrophy and fibrosis in the heart of rats treated with aldosterone for 2 months with addition of 1% NaCl and 0.3% KC1 in water. This treatment induced arterial hypertension, a moderate left ventricular hypertrophy, and a decrease in plasma thyroxine. Equatorial sections of hearts from treated rats showed numerous foci of proliferating nonmuscular cells and a biventricular fibrosis. Computerized videodensitometry demonstrated an increase of collagen volume fraction by 152% and 146% and of the ratio of the perivascular collagen area and vascular area by 86% and 167% in left and right ventricles,

Cardiac and skeletal myosin subfragments 1 cleaved into three fragments were modified by 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene-sulfonate in the presence of the nucleophile nitrotyrosine ethyl ester. The effects observed (first-order kinetics of ATPase inactivation, incorporation of 1 mol of nitrotyrosine/mol of subfragment 1) were similar to those previously observed for the nondigested subfragments 1 [Lacombe, G., Van Thiem, N., & Swynghedauw, B. (1981) Biochemistry 20, 3648-3653; Körner, M., Van Thiem, N., Lacombe, G., & Swynghedauw, B. (1982) Biochem. Biophys. Res. Commun. 105, 1198-1207]. For both native and digested subfragments 1, which were inactivated to the extent of about 70%, the location of the label nitrotyrosine was performed by immunological blotting with 125I-labeled anti-nitrotyrosine immunoglobulins. It was found that the modified residue was essentially located on the heavy chain for the native subfragments 1 and on the 50K peptide for the digested subfragments 1.