Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

apoptotic mediators such as cytochrome c, AIF and endonuclease G into the cytosol which
may further the apoptotic process (Yang and Cortopassi, 1998). This is supported by studies
which show that pharmacological inhibition of MPTP opening with cyclosporine, sangliferin
A or preconditioning reduce infarct size in rodents by 50%, suggesting that high levels of
MPTP opening is a detrimental event during I/R injury (Hausenloy et al., 2003, Javadov et
al., 2003). In agreement with this, gene targeted mice deficient in cyclophilin D, an essential
component of the MPTP, were resistant to mitochondrial permeability transition and had a
40% reduction in infarct size following I/R injury (Baines et al., 2005, Nakagawa et al.,
2005). This has recently been confirmed in humans where a small clinical study showed that
a single intravenous bolus of cyclosporine in patients with acute ST-elevation myocardial
infarction undergoing primary PCI reduced biochemical markers of cardiac dysfunction and
decreased infarct size by 20% (Piot et al., 2008). It must be noted however that MPTP may
actually be dispensable for activation of apoptosis via the mitochondrial pathway since
cyclophinin D deficient cells were found to respond normally to apoptotic stimuli (Baines et
al., 2005).
1.2.7 Reactive Oxygen Species (ROS) in Myocardial Cell Death
Another mechanism whereby reperfusion induces cell death in the myocardium is through the
generation of ROS. ROS consist of hydrogen peroxide (), the superoxide anion ( - ) and the
hydroxyl radical (·OH) amongst others. ROS can cause cellular damage in several ways,
including DNA strand breaks, lipid peroxidation and reduction of protein sulfhydryl bonds
(Goswami et al., 2007). In addition, ROS can induce apoptosis directly via peroxidation of
cardiolipin which disrupts the cytochome c–cardiolipin interaction, thereby releasing
cytochrome c into the cytosol where it induces apoptosome formation (Shidoji et al., 1999).
Under normal cellular conditions in the myocardium, 95% of oxygen is reduced to via the
mitochondrial electron transport chain. However the remaining 5% of oxygen is reduced via
the univalent pathway in which free radicals are produced, namely the superoxide anion ( - )
and its protonated form ·, these are in turn converted by superoxide dismutase (SOD) into
which is toxic at high concentrations. is further reduced to via catalase or glutathione
peroxidase, therefore the toxic superoxide radical can be safely metabolised to water (Becker,
2004). During ischaemia however, the increasing concentration of can lead to the generation
of the damaging hydroxyl radical (·OH) via the fenton reaction (Mao et al., 1993). Oxidative
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