Cardiac hypertrophy in rats after supravalvular aortic constriction. II. Inhibition of cellular autophagy in hypertrophying cardiomyocytes.

Adult male Sprague-Dawley rats were killed by retrograde perfusion fixation 3, 7, 14, 21 and 35 days after supravalvular aortic constriction (n = 33) or sham-operation (n = 25). Subepicardial specimens of the left ventricular myocardium were evaluated by conventional electron microscopic morphometry, and in addition were examined for the occurrence of autophagic vacuoles (AVs) using large test areas (3.9 X 10(4) micron 2 per animal). The quotient of mitochondrial to myofibrillar volume fraction was largely unchanged during hypertrophy but was reduced by 25% compared with controls after termination of growth at 35 days. During the process of hypertrophy which eventually led to an increase in average single cell volume of the cardiomyocytes by 78%, the volume fraction and the numerical density of AVs was significantly lower than in sham-operated rats. The most striking difference was observed 7 days after the operations, the stage at which the growth rate of the cardiomyocytes relative to controls was at its maximum of 4.5% per day. At this point the volume fraction as well as the numerical density of AVs were reduced by about 50% compared with controls. At 14 and 21 days after operation, when the relative growth rate of the hypertrophying cardiomyocytes was still 2% and 1% per day, the AV volume fraction was reduced to a lesser extent (by 47% and 28%, respectively). After termination of adaptive growth at 35 days significant differences in fractional volume and numerical density of AVs were no longer detectable. These results suggest that degradation of cytoplasmic components is inhibited in cardiomyocytes undergoing hypertrophy. Such an anticatabolic reaction seems to play an important role in establishing the positive balance of cellular metabolism generally required for growth processes.