Reduction of protein degradation and atrophy in cultured fetal mouse hearts by leupeptin.

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Abstract
The effects of certain protease inhibitors on protein turnover, atrophy and viability of cultured fetal mouse hearts were examined. Leupeptin (30 .mu.M) diminished net proteolysis by .apprx. 50% (P < 0.001) and as a consequence retarded cardiac atrophy. Hearts cultured with leupeptin for 2 days contained 19% more protein than control hearts (P < 0.02). Leupeptin did not alter microscopic appearance, pattern of contraction, rates of protein synthesis and protein leakage or levels of ATP, lactate dehydrogenase and creatine kinase. Other protease inhibitors (antipain, pepstatin, chymostatin and those from soybean and bovine lung) had little or no effect on proteolysis and did not decrease atrophy. Leupeptin inhibits intracellular cathepsin B activity. In hearts exposed to leupeptin for 48 h and then washed to remove the inhibitor, cathepsin B level was twice control, whereas three other lysosomal hydrolase activities changed little or not at all. Prolonged exposure to its inhibitor selectively increased tissue content of this lysosomal protease. These findings apparently illustrate the importance of protein breakdown in determining tissue mass. Leupeptin appears useful in studies of protein turnover, in maintaining tissues or organs in culture, and possibly in the therapy of certain diseases.