A calcium stimulated cysteine protease involved in isoproterenol induced cardiac hypertrophy

The purpose of this study was to test the relationship between biochemical and functional changes accompanying beta-agonist induced cardiac hypertrophy and the activation of a calcium stimulated cysteine protease. Because the ultrastructural and ionic changes accompanying beta-agonist induced cardiac hypertrophy are reminiscent of the actions of the calcium activated neutral protease, calpain, it was hypothesized that lowering calpain activity (by the use of an exogenous inhibitor(s)) would reduce the extent of hypertrophy. Rats (275-300 g) were randomly assigned to either a control, beta-agonist (iso) or cysteine protease inhibitor (E64c) group. Isoproterenol administration(1 mg/kg) resulted in changes for ventricular weight to body weight ratio (up arrow 19%), ventricular [RNA] (up arrow 105.6%), rate of pressure development (up arrow 22% for +dP/dt) and maximum developed left ventricular pressure (up arrow 19%) (p < 0.05) after 3 days. Calpain-like activity (assessed by microplate method) increased by 45% (p < 0.05), while [cAMP] returned to control levels (following a transient rise at 1 day; 606.03 +/- 124.1 pmol/g/wet/wt to 937.9 +/- 225 (p < 0.05)). E64e (administered 1 h prior to iso) reduced the extent of hypertrophy, from 19 to 12%, and prevented the increases in; total [RNA], left ventricular function, the initial [cAMP] increase and calpain-like activity. It is concluded that a calcium stimulated cysteine protease(s), such as calpain, may be involved in the biochemical and functional changes associated with isoproterenol induced cardiac hypertrophy.