Role of glycogen synthase kinase following myocardial infarction and ischemia–reperfusion

Abstract

Glycogen synthase kinase-3 beta (GSK3β) is principally is a glycogen synthase phosphorylating enzyme that is well known for its role in muscle metabolism. GSK3β is a serine/threonine protein Kinase, which is responsible for several essential roles in mammalian cells. This enzyme is implicated in the pathophysiology of many conditions involved in homeostasis and cellular immigration. GSK3β is involved in several pathways leading to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Increasing evidence has shown the potential importance of GSK3β in ischemic heart disease and ischemia-reperfusion pathologies. Reperfusion injury may occur in tissues after prolonged ischemia following reperfusion. Reperfusion injury can be life threatening. Reperfusion injury occurs due to a change in ionic homeostasis, excess free radical production, mitochondrial damage and cell death. There are however clear, cardiac-protective signals; although the molecular pathophysiology is not clearly understood. In normal physiology, GSK3β has a critical role in the cytoprotective pathway. However, it`s controversial role in ischemia and ischemia-reperfusion is a topic of current interest. In this review, we have opted to focus on GSK3β interactions with mitochondria in ischemic heart disease and expand on the therapeutic interventions.

GSK3β is a key regulator of the ROS-dependent necrotic death induced by the quinone DMNQ

“…We focused the attention on glycogen synthase kinase-3 β (GSK3β) for two main reasons. First GSK3β can be activated under specific stress-conditions and it is involved in the regulation of cell death pathways in different cellular contexts [23][24][25][26][27] . Second, among other represented hits interacting proteins, regulators and substrates of GSK3β were found.…”

Letter to the editor regarding article, “Role of glycogen synthase kinase following myocardial infarction and ischemia–reperfusion”

“…We humbly write to thank Zhi-Qing Chen et al for their letter where they have pointed out the miswritten difference we have reported in molecular structure in our already published paper between GSK-3α and GSK-3β2 and to express our deepest apologies for this miswritten phrase in our paper [1]. We totally agree with Zhi-Qing Chen et al that GSK-3α occupies a domain with 13 amino acids inserts at the N-terminal of GSK-3α and not GSK-3β2.…”

Mitochondrial Protection by PARP Inhibition

“…Due to its extensive participation in signalling pathways (in addition to its metabolic role of regulating glycogen synthesis), glycogen synthase kinase (GSK)-3β is one of Akt's most prominent downstream targets in mediating mitochondrial protection [76]. In hypoxia, GSK-3β is activated by phosphorylation of its Tyr 216 [77], and contributes to the hypoxia or ischemia-induced tissue injury.…”

“…The diminished binding of the transcription factor results in a reduced expression of Nrf2/ARE-regulated genes encoding proteins of the antioxidant defence system, such as superoxide dismutase, peroxidase, catalase, and enzymes of glutathione synthesis and reactivation [78]. The resulting oxidative stress damages the mitochondria, which significantly contributes to hypoxia or ischemia-induced mitochondrial impairments and tissue injury [76]. Furthermore, the activation of GSK-3β diminishes nuclear translocation of the transcription factor cAMP response element-binding protein (CREB), thereby diminishing CREB's binding to the co-activator CREB-binding protein (CBP) [79].…”

“…This process causes altered interaction with the pro-inflammatory transcription factor nuclear factor (NF)κB leading to increased inflammatory response [80]. The oxidative stress accompanying the inflammatory response contributes to mitochondrial damages [76]. Akt counteracts these harmful effects of GSK-3β by phosphorylating its Ser 9 , thereby inhibiting the enzyme [81].…”