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

While ROS production can be highly toxic and damaging to cellular structures, they also play
a role in cell signaling. A pertinent example of this is the finding that the cardioprotection
afforded by ischaemic preconditioning (brief periods of repeated ischaemia before the onset
of reperfusion) is lost in the presence of anti-oxidants and preconditioning can be mimicked
by pro-oxidants both in vitro and in vivo (Vanden-Hoek et al., 2000, Tang et al., 2002).
Therefore ROS production in cardiac myocytes can have both detrimental and beneficial
effects during I/R injury.
1.2.8 +
Overload and Contracture
In addition to apoptosis and ROS production, myocardial damage can occur via
hypercontracture following reperfusion. During ischaemia, the lack of oxygen leads to
lowered production of ATP, increased lactic acid accumulation and a lowering of the pH. In
order to try to restore the pH balance, myocytes utilise the Na + /H + exchanger to remove
excess protons, however this has the ancillary effect of increasing the intracellular Na +
concentration (Wang et al., 2000). Normally excess Na + is pumped out of the cell using the
Na + /K + -ATPase, however since ATP levels are depleted in ischaemic cells, the Na + /K + -
ATPase cannot work at full capacity. This causes the sarcolemmal Na + / + exchanger to operate
in the reverse mode, pumping out high levels of + into the cytosol, eventually resulting in
calcium overload (Allen and Xiao, 2003). In addition to this + overloaded state, the contractile
machinery of the myocyte is directly compromised due to the low ATP levels and the
myocyte will appear in a state of contracture which causes a shortening and stiffening of the
myocardium (Hohl et al., 1982). Once ATP production has been resumed upon reperfusion,
the contractile machinery is reactivated, however this often occurs faster than restoration of
normal cytosolic Ca + levels and can cause uncontrolled + dependent contraction, rapid
oscillations in +
transport from the sarcoplasmic reticulum and eventually hypercontracture
(Gustafsson and Gottlieb, 2008). In this hypercontracted state, myocytes are prone to
mechanical damage which can contribute to the spread of necrosis.
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