Role of Glycogen Synthase Kinase-3β in Cardioprotection

Abstract

Abstract-Limitation of infarct size by ischemic/pharmacological pre-and postconditioning involves activation of a complex set of cell-signaling pathways. Multiple lines of evidence implicate the mitochondrial permeability transition pore (mPTP) as a key end effector of ischemic/pharmacological pre-and postconditioning. Increasing the ROS threshold for mPTP induction enhances the resistance of cardiomyocytes to oxidant stress and results in infarct size reduction. Here, we survey and synthesize the present knowledge about the role of glycogen synthase kinase (GSK)-3␤ in cardioprotection, including pre-and postconditioning. Activation of a wide spectrum of cardioprotective signaling pathways is associated with phosphorylation and inhibition of a discrete pool of GSK-3␤ relevant to mitochondrial signaling. Therefore, GSK-3␤ has emerged as the integration point of many of these pathways and plays a central role in transferring protective signals downstream to target(s) that act at or in proximity to the mPTP. Bcl-2 family proteins and mPTP-regulatory elements, such as adenine nucleotide translocator and cyclophilin D (possibly voltage-dependent anion channel), may be the functional downstream target(s) of GSK-3␤. Gaining a better understanding of these interactions to control and prevent mPTP induction when appropriate will enable us to decrease the negative impact of the reperfusion-induced ROS burst on the fate of mitochondria and perhaps allow us to limit propagation of damage throughout and between cells and consequently, to better limit infarct size. Key Words: mitochondria Ⅲ ROS-induced ROS release Ⅲ permeability transition pore T issue reperfusion after ischemia, although ultimately necessary for cell survival, is a "double-edged sword" because it is also associated with further damage, known as reperfusion injury. 1 Once the artery blockage is removed, blood flow-triggered reoxygenation aggravates the injury experienced during the ischemia, resulting in further cell damage. A similar process can be mimicked in experimental settings, eg, in isolated cardiomyocytes or neurons exposed to prolonged hypoxia followed by reoxygenation. The lack of oxygen results in a situation in which the restoration of circulation rapidly leads to oxidative damage through the induction of excess oxidative stress. Therefore, the improvement in tissue function and survival after reperfusion has often been substantially negatively affected by this damaging phenomenon.Reperfusion-induced elevation in cytotoxic reactive oxygen species (ROS), mostly in and around mitochondria 2 (reviewed elsewhere 3,4 ) can trigger opening of the so-called mitochondrial permeability transition pore (mPTP), that is accompanied by the immediate dissipation of the mitochondrial membrane potential, ⌬ m , with detrimental consequences for the affected mitochondrion (originally proven by Griffiths and Halestrap 5 ). We have developed a method to quantify the mPTP susceptibility to ROS induction in individual mitochondria inside intact cardiomyocytes. Using t...

Glycogen Synthase Kinase 3β Inhibition Improves Myocardial Angiogenesis and Perfusion in a Swine Model of Metabolic Syndrome

“…GSK‐3β is known to phosphorylate and inhibit antiapoptotic proteins p‐Bcl‐2 (ser70) and p‐mcl‐1 (ser159) 15, 16. Mcl‐1 localizes to the mitochondria, where it interacts with and antagonizes proapoptotic Bcl‐2 family members and inhibits apoptosis.…”

GSK-3β inhibition protects mesothelial cells during experimental peritoneal dialysis through upregulation of the heat shock response

“…This key regulator of the heat shock response has been shown to be inactivated by GSK-3β by specific phosphorylation, rendering the transcription of cytoprotective genes inactive. GSK-3β itself is regulated through a phosphorylation step at the serine-9 residue by different upstream kinases (Juhaszova et al 2009). This regulation of GSK-3β is influenced by cell stressors such as hypoxia, oxidative stress, heat shock, but also by factors such as changes in glucose concentration and high GDP content.…”

ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function

“…Based on previous work by our group (Juhaszova et al, 2004;Juhaszova et al, 2009) as well as by others (Garlid et al, 2003;Halestrap, 1989;Sato et al, 1998) the following reveal key manifestations of mKATP activation in cardiomyocytes in response to KCOs: (1) flavoprotein (FP) oxidation, (2) modulation of mitochondrial regulatory swelling (i.e., due to mitochondrial K + accumulation), (3) volume activation of respiration (as a consequence of #2), (4) inhibition of GSK-3β activity via ser-9 phosphorylation, and (5) increased mPTP reactive All rights reserved. No reuse allowed without permission.…”

“…The mPTP is a key end-effector of protection signaling: the threshold for mPTP-induction by ROS being significantly reduced after ischemia-reperfusion injury and contributing to cell death, but beneficially increased by preconditioning, postconditioning and other forms of protection signaling, contributing to cell survival (Juhaszova et al, 2004;Juhaszova et al, 2009). We showed that cell protection involves convergence of a multiplicity of potential and distinct upstream pathways (including opening of mKATP), each acting via inhibition of GSK-3β on the end effector, the mPTP complex, to limit its induction (see Figure 4H-K).…”