Diabetes Abolishes Morphine-Induced Cardioprotection via Multiple Pathways Upstream of Glycogen Synthase Kinase-3β

Abstract

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-)GSK3␤ was reduced 5 min after reperfusion in DBRs compared with NDBRs (0.83 ؎ 0.29 and 1.94 ؎ 0.12 [P < 0.05] pg/g tissue, respectively). The GSK3␤ 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-GSK3␤, 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 GSK3␤. Diabetes 56:127-136, 2007

Clinical cardioprotection and the value of conditioning responses

“…Abnormal cell signaling is also in agreement with studies in diseased hearts (70,76) and with observations that increasing the amplitude of the trigger stimulus may generate protection in older hearts, for example, with additional (186) or longer (15) conditioning cycles or with enhanced protective GPCR expression (81). These latter studies confirm that protective machinery is still present in older hearts but appears ineffectively activated and harnessed.…”

“…Others demonstrated impairment of Precon-related responses in diabetic patients (127), consistent with experimental evidence of failed cardioprotection via Precon in diabetic animal models (42,43,110,122,141,218). Responses to related or pharmacological stimuli are also impaired with diabetes, including anesthetic Precon (109,209), opioid-mediated Precon (70,175), and protection in response to heat stress (104), phosphodiesterase-5 inhibition (98), or via sphingolipid-dependent PKC modulation (73). Delayed or late Precon responses may also be eliminated (49).…”

“…There are parallels between the aging effects on signaling and the effects of disease (outlined in the following sections) ( Table 1). For example, elevations in phosphatases may also be involved in impaired protection with obesity (18), while ineffective activation of kinases is also detected in diabetes (70,219). It is important to continue these investigations into protective responses and signaling in aged myocardium, as this may not only reveal more effective protective strategies for the target patient population but may also provide insights into the molecular basis of age-related changes in both physiology and the pathogenesis of heart disease.…”

Cardiac Protection by Basic Fibroblast Growth Factor from Ischemia/Reperfusion-Induced Injury in Diabetic Rats

“…It is known that antioxidant and angiogenic action of FGF are mediated by signaling pathways that involves in several other kinases, such as Akt, extracellular signal-regulated kinase (Erk1/2), and vascular endothelial growth factor (VEGF). [13][14][15][16]45) As mentioned above, diabetes impairs several antioxidants and growth factors, [17][18][19][20][21] administration of single exogenous rhbFGF alone is unable to overcome all these defectives, and consequently offered a slightly less protection in diabetic rats as compared to that in non-diabetic rats. Therefore, combination of bFGF with other growth factors may be a potential approach to optimize the protective effect of bFGF against I/R-induced cardiac injury 46) even under diabetic conditions, which will be warranty in the future studies.…”

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Multiple signalling proteins/cascades are dysregulated in the diabetic heart, including extracellular signal-regulated kinase 1 (ERK1), signal transducer and activator of transcription 3 (STAT3) and AKT (a key downstream target of PI3K) [4,[16][17][18][19]. A critical step in developing better therapeutics is to understand which signalling events represent key mechanisms in the development of cardiomyopathy in a setting of hyperglycaemia.…”