Abstract 172: Upregulation of Heat Shock Transcriptional Factor 1 Plays a Critical Role in Physiological Cardiac Hypertrophy
Exercise-induced cardiac hypertrophy has been reported to have better prognosis than pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy induced by exercise was associated with less cardiac fibrosis and better systolic function, whereas chronic pressure overload causes maladaptive hypertrophy and heart failure, suggesting that the adaptive mechanisms may exist in exercise-induced hypertrophy. Here we show a critical role of heat shock factor 1 (HSF1), an important transcription factor for heat shock proteins, in the adaptive mechanism of cardiac hypertrophy. To determine the molecular difference between exercise-induced and pressure overload-induced cardiac hypertrophy, we examined expression of 8800 genes in the heart of exercise-induced hypertrophy model using DNA chip technique and compared with pressure overload-induced hypertrophy. Expression of HSF1 and its target downstreams heat shock proteins was significantly upregurated in the heart by exercise but not by chronic pressure overload assessed by northern blot analyses and western blot analyses. To elucidate the role of HSF-1 in cardiac hypertrophy, we established a cardiac hypertrophy model by constricting transverse aorta (TAC) for 4 weeks in HSF-1 transgenic mice that express constitutively active HSF1 and compared with wild-type mice. Constitutive activation of HSF1 in the heart significantly ameliorated death of cardiomyocytes and cardiac fibrosis and thereby prevented cardiac dysfunction, suggesting a protective role of HSF1 against maladaptive hypertrophy. We next determined whether disruption of HSF1 causes maladaptive hypertrophy during exercise. We produced the exercise-induced cardiac hypertrophy model in HSF1-deficient heterozygote mice and compared them with their littermate wild-type mice. HSF1-deficient heterozygote mice failed to induce expression of heat shock proteins in the heart and thus promoted cardiac dysfunction in response to exercise, a load that normally leads to adaptive hypertrophy with preserved systolic function. These results suggest that HSF1 has a critical role in regulating the transition between adaptive and maladaptive hypertrophy.