Protective effect of transgenic expression of porcine heat shock protein 70 on hypothalamic ischemic and oxidative damage in a mouse model of heatstroke.
BACKGROUND
Transgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70beta gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke.


RESULTS
We report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4 degrees C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2 degrees C +/- 0.4 degrees C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4 degrees C +/- 0.3 degrees C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression.


CONCLUSIONS
This study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.
Chen
Zhih-Cherng
ZC
Section of General Medicine, Chi Mei Medical Center, Tainan, Taiwan, Republic of China. z_cchen@yahoo.com.tw
Wu
Wen-Shian
WS
Lin
Mao-Tsun
MT
Hsu
Chuan-Chih
CC
D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D003720:Densitometry; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018883:Heat Stroke / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D007031:Hypothalamus / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D007035:Hypothermia / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D018384:Oxidative Stress / Q000502:physiology*; D013552:Swine
D016207:Cytokines; D050884:HSP72 Heat-Shock Proteins; D018696:Neuroprotective Agents