Activation of the heat shock response:: relationship to energy metabolites.: A 31P NMR study in rat hearts

Heat shock factor (HSF), the transcription factor for the heat shock proteins, is activated by cardiac ischemia, but the mechanism of activation is unknown. Ischemia is accompanied by changes in the energy state and acid-base conditions. We hypothesized that decreased ATP and/or intracellular pH (pH(i)) might activate HSF. To test this hypothesis, we perfused rat hearts within an NMR spectrometer. NMR data showed that after 6.5, 13, and 20 min of ischemia, ATP dropped to 62.7, 23.1, and 6.9% of the control level, and pH(i) was 6.16, 5.94, and 5.79, respectively. Reperfusion after ischemia partially restored ATP levels, and this was associated with greater activation of HSF1. HSF1 was also activated after 6.5 min of ischemia. Activation of HSF1 was less after 13 min of ischemia and barely detectable after 20 min of ischemia. In conclusion, 1) a moderate decrease in intracellular ATP correlates with activation of HSF1 in the heart; and 2) a severe depletion in ATP correlates with an attenuation in HSF1 activation, and the restoration of ATP leads to greater activation of HSF1, suggesting that a critical ATP level is required for activation of HSF1.