Gross Eric R, Hsu Anna K, Gross Garrett J
Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
Diabetes. 2007 Jan;56(1):127-36. doi: 10.2337/db06-0907.
The cardioprotective effect of opioids or glycogen synthase kinase (GSK) inhibitors given at reperfusion has not been investigated in diabetes models. Therefore, nondiabetic (NDBR) or streptozotocin-induced diabetic (DBR) rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Groups of NDBR or DBR were administered either vehicle, morphine (0.3 mg/kg), or the GSK inhibitor SB216763 (0.6 mg/kg) 5 min before reperfusion. SB216763 (but not morphine) reduced infarct size in DBRs (44 +/- 1* and 55 +/- 2%, respectively), while both agents reduced infarct size in NDBRs versus untreated NDBRs or DBRs (44 +/- 3*, 42 +/- 3*, 60 +/- 2, and 56 +/- 2%, respectively, *P < 0.001). Morphine-induced phospho- (P-)GSK3beta was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 +/- 0.29 and 1.94 +/- 0.12 [P < 0.05] pg/microg tissue, respectively). The GSK3beta mediators, P-Akt, P-extracellular signal-related kinase (ERK)1, and P-signal transducer and activator of transcription (STAT)3, were also significantly reduced in untreated DBR compared with NDBR rats. Morphine-induced elevations of P-Akt, P-ERK1, P-p70s6, P-janus-activated kinase-2, and P-STAT3 in NDBRs were also blunted in DBRs. H9C2 cells raised in 25 mmol/l compared with 5.56 mmol/l glucose media also demonstrated reduced morphine-induced P-GSK3beta, P-Akt, P-STAT3, and P-ERK1 after 15 min. Hence, acute GSK inhibition may provide a novel therapeutic strategy for diabetic patients during an acute myocardial infarction, whereas morphine is less effective due to signaling events that adversely affect GSK3beta.
在糖尿病模型中,尚未对再灌注时给予阿片类药物或糖原合酶激酶(GSK)抑制剂的心脏保护作用进行研究。因此,对非糖尿病(NDBR)或链脲佐菌素诱导的糖尿病(DBR)大鼠心脏进行30分钟的缺血和2小时的再灌注。在再灌注前5分钟,给NDBR或DBR组分别注射溶媒、吗啡(0.3mg/kg)或GSK抑制剂SB216763(0.6mg/kg)。SB216763(而非吗啡)可减小DBR的梗死面积(分别为44±1%和55±2%),而与未治疗的NDBR或DBR相比,两种药物均可减小NDBR的梗死面积(分别为44±3%、42±3%、60±2%和56±2%,P<0.001)。与NDBR相比,再灌注5分钟后,DBR中吗啡诱导的磷酸化(P-)GSK3β降低(分别为0.83±0.29和1.94±0.12[P<0.05]pg/μg组织)。与NDBR大鼠相比,未治疗的DBR中GSK3β介质P-Akt、P-细胞外信号调节激酶(ERK)1和P-信号转导子和转录激活子(STAT)3也显著降低。DBR中吗啡诱导的NDBR中P-Akt、P-ERK1、P-p70s6、P-janus激活激酶-2和P-STAT3升高也减弱。与在5.56mmol/L葡萄糖培养基中培养的H9C2细胞相比,在25mmol/L葡萄糖培养基中培养的H9C2细胞在15分钟后也显示吗啡诱导的P-GSK3β、P-Akt、P-STAT3和P-ERK1降低。因此,急性GSK抑制可能为急性心肌梗死期间的糖尿病患者提供一种新的治疗策略,而由于信号事件对GSK3β产生不利影响,吗啡的效果较差。