Pharmacological postconditioning with atorvastatin calcium attenuates myocardial ischemia/reperfusion injury in diabetic rats by phosphorylating GSK3β

Abstract

Diabetes is an independent risk factor for myocardial ischemia, and many epidemiological data and laboratory studies have revealed that diabetes significantly exacerbated myocardial ischemia/reperfusion injury and ameliorated protective effects. The present study aimed to determine whether pharmacological postconditioning with atorvastatin calcium lessened diabetic myocardial ischemia/reperfusion injury, and investigated the role of glycogen synthase kinase (GSK3β) in this. A total of 72 streptozotocin-induced diabetic rats were randomly divided into six groups, and 24 age-matched male non-diabetic Sprague-Dawley rats were randomly divided into two groups. Rats all received 40 min myocardial ischemia followed by 180 min reperfusion, except sham-operated groups. Compared with the non-diabetic ischemia/reperfusion model group, the diabetic ischemia/reperfusion group had a comparable myocardial infarct size, but a higher level of serum cardiac troponin I (cTnI) and morphological alterations to their myocardial cells. Compared with the diabetic ischemia/reperfusion group, the group that received pharmacological postconditioning with atorvastatin calcium had smaller myocardial infarct sizes, lower levels of cTnI, reduced morphological alterations to myocardial cells, higher levels of p-GSK3β, heat shock factor (HSF)-1 and heat shock protein (HSP)70. The cardioprotective effect conferred by atorvastatin calcium did not attenuate myocardial ischemia/reperfusion injury following application of TDZD-8, which phosphorylates and inactivates GSK3β. Pharmacological postconditioning with atorvastatin calcium may attenuate diabetic heart ischemia/reperfusion injury in the current context. The phosphorylation of GSK3β serves a critical role during the cardioprotection in diabetic rats, and p-GSK3β may accelerate HSP70 production partially by activating HSF-1 during myocardial ischemic/reperfusion injury.

Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway

“…Meanwhile, plasma CK-MB and LDH levels in the DM-DW group were increased compared to the DM-D group, suggesting that cardioprotection of DEX were suppressed by Wort. However, the aforementioned index in the DM-S group was similar to the S group, and no significant difference was observed between DM-S and S groups, indicating that a 4-week diabetic state may not significantly influence cardiac function, which was consistent with a previous study [ 25 ], while Mokhtari et al reported that STZ-induced diabetes at the 10th week significantly increases the level of cTnI and exacerbates the myocardial injury [ 26 ]. Besides, prior studies have noted that a diabetic heart is more sensitive to ischemic injury [ 26 , 27 ], while Aasum et al [ 28 ] have reported that the in vitro diabetic rat heart was less sensitive to myocardial I/R injury 6 weeks after STZ administration, while at 12th week, cardiac function was significantly impaired.…”

“…The phosphorylation of Akt in the DM-S group was not different from the S group, which was not consistent with the Wang et al study, which reported that the signaling pathway was impaired in the diabetic myocardium, with a lower level of basal Akt phosphorylation than normal rats [ 27 ]. The phosphorylation of GSK-3 β was decreased in the DM-S group compared with the S group, suggesting that p-GSK-3 β was inactivated in the diabetic state, which was confirmed by a prior study [ 25 ]. Mokhtari et al [ 26 ] confirmed that at the 10th week of diabetes induction, phosphorylation of GSK-3 β in the DM-I/R group was significantly less than the I/R group, suggesting that diabetes impairs the intracellular signaling pathways and increases cardiac injury as compared to normal hearts; however, no significant difference was seen between I/R and DM-I/R groups in our study.…”

Heat shock protein 70: A promising therapeutic target for myocardial ischemia–reperfusion injury

“…Presently, a large number of studies have reported that HSP70 is induced by preconditioning, including IPC (Hampton et al, ), RIPC (Vicencio et al, ), LPS (Shimizu et al, ), pharmacological (S. Guo, Gao, et al, 2018), and physical preconditioning (Uryash et al, ) and serves as a key mediator enhancing myocardia stress adaption to I/R injury (Figure ). In addition, postconditioning has also been revealed to alleviate I/R injury via inducting HSP70 (L. Chen, Cai, Cheng, Zhang, & Fang, ). Hereinafter, we mainly focus on HSP70‐induced cardioprotective effects against I/R injury in the presence of preconditioning and postconditioning.…”

Myocyte membrane and microdomain modifications in diabetes: determinants of ischemic tolerance and cardioprotection

“…Nonetheless, there are some reports of preserved protection in models of T1DM, including exercise [ 136 ] and ischemic preconditioning [ 86 ], while Potier et al [ 108 ] identify a specific shift to protective efficacy of B2 bradykinin receptors in T2DM hearts (vs. B1 receptors in non-DM tissue). Atorvastatin is also reportedly cardioprotective in T1DM rats [ 137 ], involving a glycogen synthase kinase 3β (GSK3β) dependent protection linked to heat shock factor 1 and heat shock protein 70 (HSP70).…”