Inhibitive Effects of Low Oxygen and Glucose Deprivation on Brain-Pancreas Relative Protein Expression via Hypoxia- Inducible Factor-1 Pathways

Abstract

Background: Brain-Pancreas Relative Protein (BPRP), a novel protein discovered in our lab, was decreased in ischemic rat brain. However, the mechanisms regulating BPRP expression during ischemia need further investigation. Methods: In the present study we cultured PC12 cells with low oxygen and glucose deprivation (LOGD, a model of ischemia in vitro) media, then examined the signal transduction pathways of BPRP expression under LOGD. Results: It was found that LOGD significantly decreased BPRP expression, but increased the intracellular Ca²⁺ concentration ([Ca²⁺]_i), p38 mitogen-activated protein kinases (MAPK) phosphorylation and hypoxia inducible factor 1 α subunit (HIF-1α) expression. However, BAPTA-AM (an intracellular calcium chelator), SB 203580 (an inhibitor of p38) and HIF-1α antisense significantly inhibited the [Ca²⁺]_i, p38 MAPK phosphorylation and HIF-1α expression respectively. Our results also showed that p38 MAPK phosphorylation was reduced by BAPTA-AM, and HIF-1α expression was inhibited by SB203580 and BAPTA-AM, suggesting that calcium, p38 MAPK and HIF-1α are in the same signal transduction pathways during LOGD. Noticeably, reduced BPRP expression by LOGD can be recovered by SB203580, BAPTA-AM and HIF-1α antisense. Conclusion: All together, our observations suggest that calcium, p38 MAPK activation and HIF-1α are necessary for LOGD-reduced BPRP expression in PC12 cells.