Restoration of calcium handling properties of adult cardiac myocytes from hypertrophied hearts

Reductions in cardiac sarcoplasmic reticulum calcium-ATPase (Serca2a) levels are thought to underlie the prolonged calcium (Ca2+) transients and consequent reduced contractile performance seen in human cardiac hypertrophy and heart failure. In freshly isolated cardiac myocytes from rats with monocrotaline-induced right ventricular hypertrophy we found reduced sarcoplasmic reticulum Serca2a expression and prolonged Ca2+ transients, characteristic of hypertrophic cardiac disease. Modulation of intracellular Ca2+ levels, Ca2+ kinetics or Ca2+ sensitivity is the focus of many current therapeutic approaches to improve contractile performance in the hypertrophic or failing heart. However, the functional effects of increasing Serca2a expression on Ca2+ handling properties in myocytes from an animal model of cardiac hypertrophy are largely unknown. Here, we describe enhancement of the deficient Ca2+ handling properties evident in myocytes from hypertrophied hearts following adenoviral-mediated transfer of the human Serca2a gene to these myocytes. Serca2a gene transfer resulted in a marked over-expression of Serca2a and completely restored the time-course of the stimulated Ca2+ responses to that seen in control cells without altering diastolic Ca2+ values or Ca2+ transient amplitudes. These results highlight the importance of Serca2a deficiencies in the hypertrophic phenotype of cardiac muscle and suggest a simple, effective approach for manipulation of normal cardiac function. (C) 2001 Harcourt Publishers Ltd.