Role of glycogen synthase kinase-3beta in cardioprotection

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)-3beta 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-3beta relevant to mitochondrial signaling. Therefore, GSK-3beta 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-3beta. 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.

Figure 1. Scheme of enzyme-signaling-dependent protection against mPTP-induction

Memory-associated protection (left), induced by triggers conveying upstream signaling either via kinases (including AKT, eNOS, guanylyl cyclase, PKG and PKC; not shown), or acting directly, engages mitochondrial targets associated with an increased K⁺-influx into, or retention by, mitochondria (induced by mitoKATP openers, inhibitors of mitochondrial K⁺/H⁺ exchange, as well as by agents that may increase K⁺-influx into mitochondria via other channels, such as BK_Ca), consequent regulatory mitochondrial matrix swelling, increased respiration producing a redox signal due to moderately increased ROS production which results in local PKC activation. Activated PKC, in turn, signals in a positive-feedback loop to mitoKATP producing the system memory which enables sustained (∼hours) inhibition of GSK-3β and consequent prolonged protection against mPTP-induction. Memory-lacking protection (right) triggered by a multitude of cell-surface receptor ligands or pharmacologic agents causing activation of diverse signaling pathways (e.g., PKA, PKB, PKC, PKG) that can bypass the mitochondrial volume regulatory mechanism and still converge on GSK-3β resulting in relatively short term protection of mPTP, determined, in part, by the duration of exposure to the triggering signal.

Figure 2. Proposed model of mPTP modulation by GSK-3β

The phosphorylation state of the mitochondrial-(ANT)-associated pool of GSK-3β contributes to the balance of Bcl-2-family protein effects, the result of which determines the resistance of the mPTP to oxidant stress. Basal state (top): the local GSK-3β pool (active in the basal state) binds ANT in a complex with phosphorylated VDAC, CyP-D and possibly other mPTP-regulatory elements. The basal state is established by the mutual antagonism holding in check the activities of the “anti-apoptotic” BH4 and the “de-repressor” BH3-only domain Bcl-2 protein family members. Note that certain direct inhibitors of GSK-3β do not necessarily change GSK-3β activity via phosphorylation-related mechanisms. Protection state (bottom): the protection signal induces inactivation/phosphorylation of this GSK-3β subdomain pool resulting in a shift in interaction within the mPTP regulatory complex elements because of subsequent modulation of the balance between opposing Bcl-2 family members in favor of the “anti-apoptotic” elements with consequent protection being manifested by an increase in mPTP-ROS threshold (modified from10).