Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 254

Moreover, considering that ATP is required not only for chaperone
function but also IRE1 activation, changes in cellular energy metabolism
may influence the development and maintenance of the UPR ( Burkart
et al., 2011 ). During the onset of cardiac hypertrophy, it is not clear whether
changes in fatty acid metabolism and ATP levels occur in cardiomyocytes.
However, while studies of physiological hypertrophy suggest an increase in
fatty acid metabolism ( Burelle et al., 2004 ; Strøm et al., 2005 ), this contrasts
with the decrease observed during pathological hypertrophy ( van Bilsen
et al., 2009 ; Doenst et al., 2010 ; Abel and Doenst, 2011 ). However, these
changes are still controversial since other studies suggest that during patho-
logical hypertrophy, there are no metabolic changes in cardiac cells ( Degens
et al., 2006 ).
Thus, while at the onset cellular metabolism may remain unchanged and
UPR may represent part of a cellular adaptation process, persistent stress
along with other unknown factors, such as changes in energy levels, could
induce a switch from protective ER stress signaling to cell death.
Thus, along with the activation of ER stress, both apoptosis and loss of
cardiac function can be observed in the progression from hypertrophy to
heart failure. Indeed, ER stress is involved in cardiotoxicity and progres-
sion of heart disease to heart failure ( Groenendyk et al., 2010 ; Minamino
et al., 2010 ). Furthermore, cardiac dysfunction is generally associated with a
decrease in the cellular energy ( Groenendyk et al., 2010 ; Schulz et al., 2010 ;
Dickhout et al., 2011 ; Ni et al., 2011 ).
While various studies report on activation of the UPR in both hyper-
trophied and failing hearts, activation of proapoptotic CHOP-induced ER
stress has only been reported for heart failure or during transition from
hypertrophy to failure. Also, for CHOP knockout mice, decreased degrees
of hypertrophy and cardiac dysfunction are observed after transverse aortic
constriction in comparison to wild-type animals ( Okada et al., 2004 ; Min-
amino et al., 2010 ). On the other hand, during pressure overload-induced
ER stress, SREBP1c is activated, which in turn induces the synthesis of
triglycerides, while the activation of XBP-1 stimulates the synthesis of
phosphatidylcholine. These observations, in conjunction with reduced fatty
acid oxidation that induces triglyceride accumulation in cardiomyocytes,
may contribute to lipotoxicity that has been described in the heart failure
( Okada et al., 2004 ; Groenendyk et al., 2010 ).
Clearly, further studies are required to clarify the relationship between
induction of ER stress in the heart, development of cardiac hypertrophy
and progression to heart failure. Similarly, the relationship between UPR