Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 253

an inducible ATF6 overexpression model discovered that UPR induction
favors cardiomyocyte survival during IR, by reducing necrosis and apoptosis
( Martindale et al., 2006 ). More studies are warranted to define the biologi-
cal role of the UPR in IR of the heart.
In summary, despite all the genetic and pharmacological data that
seek to establish a direct correlation between IR, ER stress and UPR,
a definitive conclusion is still lacking, mainly due to recent results that
point to the UPR as an adaptive response under these conditions and
not as a cell death pathway per se. Moreover, given the importance of
the metabolic changes observed during the development of IR injury,
future studies should not only focus on clarifying the metabolic regu-
lation exerted by the ER, but also recognize the importance of this
organelle in the control of the cellular homeostasis and how this affects
cellular survival.
6.2.2. Cardiac Hypertrophy and Heart Failure
It has been widely reported that both ER stress and UPR are activated in
models where pressure or volume overload or mechanical stress are used
to induce hypertrophy and heart failure ( Okada et al., 2004 ; Groenen-
dyk et al., 2010 ; Minamino et al., 2010 ; Sari et al., 2011 ). Initially, cardiac
hypertrophy is characterized as an adaptive response of the heart to over-
load. In general terms, if the stress persists, contractile dysfunction ensues
and the process is termed pathological hypertrophy . However, if contractile
function is not affected, the alterations observed are considered as physi-
ological hypertrophy. At the cellular level, hypertrophy is characterized
by an increase in the number and organization of sarcomeres, increased
protein synthesis and reexpression of genes typically observed in embry-
onic stages. In addition, all these changes are accompanied by alterations in
both calcium homeostasis and metabolism, which, together with increased
protein synthesis, can induce ER stress and consequently trigger the UPR
( Berridge, 2006 ; Abel and Doenst, 2011 ; Dickhout et al., 2011 ; Ni et al.,
2011 ).
Some studies report that during hypertrophy induced by pressure over-
load, there is an increase in BiP/GRP78 synthesis and in the activation
of the XBP1, IRE1α/TRAF2 pathways ( Dickhout et al., 2011 ; Sari et al.,
2011 ). Alternatively, activation of the fetal gene expression program charac-
teristic of hypertrophy can be altered by ATF6 and XBP-1 by modulating
the activation of key transcription factors characteristic of this disease, such
as MEF2C, NFAT and GATA ( Groenendyk et al., 2010 ).