Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury

Abstract

Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca(2+)), which further accelerates ATP depletion. The rise in Ca(2+) during ischemia and reperfusion leads to mitochondrial Ca(2+) accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however, damage to the electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca(2+) overload and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca(2+) overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca(2+) overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca(2+) overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals are discussed in detail.

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

“…A major mitochondrial death pathway is elicited by apoptotic Bcl-2 family proteins such as Bax and Bak and/or the mitochondrial permeability transition pore (mPTP), a mega channel formed at the mitochondrial inner membrane. [86][87][88][89][90] Activated Bax/Bak forms a pore at the mitochondrial outer membrane (MOM) resulting in a release of apoptotic factors from the intra-membrane space. 86,91 MitoHK-II antagonizes apoptotic Bcl-2 family proteins and thereby protects cells against apoptotic stimuli.…”

“…Mitochondrial Ca 2+ Figure 2 Regulation of HK-II expression mediated by Akt/mTORC1 pathway Interaction of hexokinase II and Akt/mTOR pathway DJ Roberts and S Miyamoto overload and/or ROS induce opening of the mPTP, resulting in a large amplitude permeability of the inner membrane, consequent rupture of the outer mitochondrial membrane and resultant necrotic (and somewhat apoptotic) cell death. [86][87][88][89][90] Majewski et al 93 demonstrated that mitoHK-II provides cellular protection against Ca 2+ overload even in Bax and Bak double-knockout cells. We and others have also reported that an increase in mitoHK-II has an inhibitory effect on Ca 2+ -and ROS-induced mPTP opening and that a large dissociation of mitoHK-II sensitizes mPTP opening and cell death.…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…In terms of cardiac protection via GPCR agonism/ischaemic preconditioning, ROS generation (via NADPH oxidase activity, mitochondrial electron transport chain) has been localised both up-and downstream of mitochondrial KATP channels and PKC (Hausenloy and Yellon, 2006;Murphy and Steenbergen, 2008;Heusch, 2015). However, ROS are also important in MMP activation and EGFR ligand shedding (Wetzker and Bohmer, 2003).…”

“…The enzyme is widely implicated in protective responses to preconditioning and GPCR stimuli (including PKC- - , and ), though some controversy remains regarding the involvement and protective functions of PKC (Hausenloy and Yellon, 2006). Within conventional protective signalling, PKC has been localised downstream of PI3K/Akt and NO/PKG and potentially both up-and downstream of mitochondrial KATP channels, with activation involving ROS generation (Hausenloy and Yellon, 2006;Murphy and Steenbergen, 2008;Heusch, 2015). Studies of preconditioning also localise PKC upstream of RTK activity (Baines et al, 1998), consistent with a role in regulating EGFR function and binding.…”

Cardiac purinergic signalling in health and disease

“…Activation by adenosine of the reperfusion injury salvage kinase pathway, involving phosphorylation of Akt and/or ERK1/2, which leads to inhibition of mitochondrial permeability transition pore formation [536][537][538], may be involved. Genetic deletion of A1R limits myocardial ischaemic tolerance [539].…”