Important role of 72-kd heat shock protein expression in the endothelial cell in acquisition of hypoxic-ischemic tolerance in the immature rat

OBJECTIVES: Hypoxic-ischemic tolerance can be induced in neonatal rats thro ugh hyperthermic preconditioning. The purposes of this study were to determ ine the interval between hyperthermic preconditioning and a subsequent hypo xic-ischemic insult that would provide optimal neuroprotection against the insult and to examine the relationship between tolerance induction and heat shock protein expression. STUDY DESIGN: On postnatal day 7 Wistar rat pups were separated into the fo llowing 2 groups: a heated group (those exposed to 15 minutes of hypertherm ic pretreatment at a brain temperature of 41.5 degrees C-42.0 degrees C) an d an unheated control group. At 6, 12, 24, 48, and 72 hours after the hyper thermic stress, rats from both groups were exposed to left carotid artery l igation followed by 2 hours of hypoxia (8% oxygen and 92% nitrogen) at 33 d egrees C. Twenty animals from each group were used at each time point. All rats were killed at 1 week after hypoxia-ischemia, at which time the brains were processed and neuronal damage in the cortex and hippocampus was asses sed histologically. Another set of 7-day-old rats (n = 30) was studied immu nohistochemically at 6, 12, 24, 48, and 72 hours after the same hyperthermi c treatment. Expression of 72-kd heat shock protein was measured in neurona l, glial, and vascular endothelial cells. RESULTS: Hyperthermia-induced hypoxic-ischemic tolerance was observed at 6, 12, and 24 hours but not at 48 and 72 hours after hyperthermic preconditio ning. Heat shock protein 72 expression in the vascular endothelial cells, r ather than in the glial or neuronal cells, was most strongly associated wit h hypoxic-ischemic tolerance. CONCLUSION: These findings suggest that heat shock protein 72 in endothelia l cells plays an important role in the acquisition of hypoxic-ischemic tole rance at postnatal day 7, a time when maximal angiogenesis occurs and the b lood-brain barrier is still immature.