Role of JAK2/STAT3 signaling pathway in brain injury induced by myocardial ischemia-reperfusion in diabetic rats

Abstract

Objective To evaluate the effects of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway on the brain injury induced by myocardial ischemia-reperfusion (I/R) in diabetic rats. Methods Pathogen-free male Sprague-Dawley rats, weighing 200-220 g, were used in this study.Diabetes mellitus was induced by intraperitoneal 1% streptozotocin 60 mg/kg and confirmed by blood glucose level ≥16.7 mmol/L 3 days later.Twenty-four rats with diabetes mellitus were randomly allocated into 3 groups (n=8 each) using a random number table: sham operation group (group S), I/R group, and myocardial I/R + AG490 (JAK inhibitor) group (group IA). Myocardial I/R was induced by occlusion of the anterior descending branch of the left coronary artery for 30 min, followed by 120 min of reperfusion in the rats anesthetized with pentobarbital sodium.AG490 3 mg/kg was injected intravenously at 20 min before reperfusion in group IA.The rats were sacrificed at 120 min of reperfusion, and the brains were removed for determination of caspase-3 and nuclear factor kappa B (NF-κB) activities (using colorimetric method), cell apoptosis (by TUNEL), and expression of interleukin-1 (IL-1), IL-6, IL-8, Bax, Bcl-2, cytochrome C (Cyt c), phosphorylated JAK2 (p-JAK2), and phosphorylated STAT3 (p-STAT3) (by Western blot). Apoptosis index was calculated. Results Compared with group S, the expression of Bax, Cyt c, IL-1, IL-6, IL-8, p-JAK2 and p-STAT3 was significantly up-regulated, the expression of Bcl-2 was down-regulated, and NF-κB and caspase-3 activities and apoptosis index were increased in I/R and IA groups (P<0.05). Compared with group I/R, the expression of Bax, Cyt c, IL-1, IL-6, IL-8, p-JAK2 and p-STAT3 was significantly down-regulated, the expression of Bcl-2 was up-regulated, and NF-κB and caspase-3 activities and apoptosis index were decreased in group IA (P<0.05). Conclusion Inflammatory responses mediated by JAK2/STAT3 signaling pathway are involved in the brain injury induced by myocardial I/R in diabetic rats. Key words: Janus kinase 2; STAT3 transcription factor; Diabetes mellitus; Myocardial reperfusion injury; Brain injuries