Lee, W. C., H. C. Wen, C. P. Chang, M. Y. Chen and M. T. Lin. Heat shock protein 72 overexpression protects against hyperthermia, circulatory shock and cerebral ischemia during heatstroke. J Appl Physiol 00: 0000-0000, 2006. This study extends our earlier studies in rats by applying our heatstroke model to a new species. Additionally, transgenic mice are used to examine the role of HSP72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70i gene ([+]HSP72), transgene-negative littermate controls ([-]HSP72), and normal Institute of Cancer Research strain mice (ICR) under pentobarbital anesthesia were subjected to heat stress (40°C) to induce heatstroke. In [-]HSP72 or ICR, the values for mean arterial pressure, the striatal blood flow, and the striatal PO₂ after the onset of heatstroke were significantly lower than those in pre-heat controls. The core and brain temperatures, the extracellular concentrations of ischemic and injury markers in the striatum, and the striatal neuronal damage scores were significantly greater than those in the pre-heat controls. In [-]HSP72 or ICR, the body temperatures, cell ischemia content and injury marker, in the striatum were significantly higher, and the mean arterial pressure, striatal blood flow and striatal PO₂ concentration were significantly lower during heatstroke than in [+]HSP72. Accordingly, the latency and the survival times for [+]HSP72 significantly exceeded those of [-]HSP72 or ICR. These results demonstrate that the overexpression of HSP72 in multiple organs improves survival during heatstroke by reducing hyperthermia, circulatory shock, and cerebral ischemia and damage in mice.