Heat shock protein 72 inhibits c-Jun N-terminal kinase 3 signaling pathway via Akt1 during cerebral ischemia

• Published in: Journal of the neurological sciences Vol. 317; no. 1; pp. 123 - 129
• Main Authors: Qi, Dashi, Liu, Hongzhi, Niu, Jian, Fan, Xing, Wen, Xiangru, Du, Yang, Mou, Jie, Pei, Dongsheng, Liu, Zhian, Zong, Zhimin, Wei, Xianyong, Song, Yuanjian
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.06.2012; Elsevier
• Subjects: AKT protein; AKT1 protein; Animals; Biological and medical sciences; Brain injury; Brain Ischemia - metabolism; Brain Ischemia - prevention & control; c-Jun amino-terminal kinase; c-Jun N-terminal kinase 3; c-Jun protein; Caspase-3; Cell survival; Cerebral blood flow; Cerebral ischemia; Heat shock protein 72; Heat shock proteins; HSP72 Heat-Shock Proteins - biosynthesis; HSP72 Heat-Shock Proteins - physiology; Hsp72 protein; Immunoblotting; Infusions, Intraventricular; Ischemia; JNK3 protein; Male; MAP Kinase Signaling System - genetics; Medical sciences; Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 10 - physiology; Neurology; Neuroprotection; Oligonucleotides; Oligonucleotides, Antisense - administration & dosage; Phosphorylation; Protein kinase B; Proto-Oncogene Proteins c-akt - physiology; Rats; Rats, Sprague-Dawley; Signal transduction; Stroke; Transcription factors; Vascular diseases and vascular malformations of the nervous system; Cerebral ischemia; c-Jun N-terminal kinase 3; Protein kinase B; Heat shock protein 72; Nervous system diseases; Enzyme; Transferases; Akt protein kinase; Cardiovascular disease; Cerebral disorder; Vascular disease; Signal transduction; Kinase; C-Onc gene; Central nervous system disease; Heat shock protein; Brain ischemia; Cerebrovascular disease
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/j.jns.2012.02.011

Abstract Although recent researches show that Heat Shock Protein 72 (HSP72) plays an important role in neuronal survival, little knowledge is known about the precise mechanisms during cerebral ischemia/reperfusion (I/R). Our present study investigated the neuroprotective mechanisms of HSP72 against ischemic brain injury induced by cerebral I/R. Mild heat shock pretreatment was employed to induce the overexpression of HSP72 by immersing rats into the water bath at 42 °C for 20 min before cerebral I/R. HSP72 antisense oligodeoxynucleotides (ODNs) were used to inhibit HSP72 expression by intracerebroventricular infusion once per day for 3 days before cerebral I/R animal model was induced by four-vessel occlusion for 15 min transient ischemia and then reperfused for various time in Sprague–Dawley rats. Immunoprecipitation and immunoblotting were used to detect the expression of the related proteins. HE-staining and TUNEL-staining were carried out to examine the neuronal death of hippocampal CA1 region. Results showed that mild heat shock could increase the phosphorylation of protein kinase B (Akt), inhibit the assembly of MLK3–MKK7–JNK3 signaling module, diminish the phosphorylation of JNK3 and c-Jun, and decrease the activation of caspase-3. Furthermore, mild heat shock could significantly protect neurons against cerebral I/R. Whereas, all of the aforementioned effects of mild heat shock were reversed by HSP72 antisense ODNs. In summary, our results imply that Akt1 activation is involved in the neuroprotection of HSP72 against ischemic brain injury via suppressing JNK3 signaling pathway and provide a new experimental foundation for stroke therapy.