Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 252

cardiomyocytes from cell death. While a detailed understanding of the role
of the UPR in ischemic heart disease remains to be established, an emerg-
ing concept is that initial low levels of UPR appear to be beneficial and
favor adaptive responses, whereas persistent ER stress is detrimental for cell
survival.
Reperfusion is the only means to terminate continuous lethal conse-
quences of an ischemic insult. This process, however, comes at a price as
reperfusion has been shown to trigger additional damage. Recently, the
UPR has been implicated in ischemia reperfusion (IR) ( Groenendyk et al.,
2010 ). All available evidence suggests the UPR is strongly activated during
IR ( Minamino et al., 2010 ). In cultured cardiomyocytes exposed to condi-
tions simulating IR, significant activation of BiP/GRP78, CHOP, ATF6
and Xbp1s is observed ( Ngoh et al., 2009 ; Yeh et al., 2010 ). These in vitro
observations have been corroborated in vivo in mouse and rat models
( Miyazaki et al., 2011 ; Tao et al., 2011 ).
Mechanistically, increased ROS levels observed upon reestablishing of
oxygen and nutrient supply, as well as rebooting mitochondrial energy
production, are likely to stimulate the UPR. Indeed, suppression of ROS
production effectively eliminates IR injury and UPR markers are dra-
matically decreased. Recent evidence suggested that ROS are an integral
component in some types of the UPR and contribute there to activating
proapoptotic pathways ( Santos et al., 2009 ). UPR inducers can effectively
increase ROS formation and knockdown of the proapoptotic branches of
the UPR is associated with a drop in ROS levels.
As for the role of the UPR in IR, most studies to date propose models
based on the correlation observed using genetic and pharmacological strat-
egies to improve cardiac recovery following IR. While these data provide
substantial support for the involvement of the UPR in IR, conclusive results
are hard to obtain. The increase in O-GlcNAc modifications can inhibit
IR-provoked cardiomyocyte death, which is associated with a decrease in
the UPR signaling ( Ngoh et al., 2009 ). Similar results have been obtained
using AMPK activators and Apelin ( Yeh et al., 2010 ; Tao et al., 2011 ). More-
over, recent studies found that IR injury is significantly decreased in mice
lacking CHOP ( Miyazaki et al., 2011 ). While these data point toward a
detrimental role for UPR in IR injury, other findings lead to alternative
conclusions. Natarajan et al. (2009) found that prolyl hydroxylase inhibi-
tion can attenuate IR injury, which may be mediated by UPR induction.
Acute induction of the UPR by brief exposure to a UPR inducer effec-
tively protects the heart from IR insult ( Petrovski et al., 2011 ). Studies using