Authored by Zakaria A Almsherqi
Mitochondria provide cellular energy
through oxidative phosphorylation, but as an integral part of this
process, superoxides and other reactive
oxygen species (ROS) are also produced. When the balance between the
production of free radicals and antioxidant capacity of the cardiac
cells
altered, oxidative stress is induced. Oxidative stress has been linked
to the development of ischemic heart disease, atherosclerosis,
congestive heart
failure, ischemic-reperfusion injury, and vascular endothelial
dysfunction. Although several clinical trials over the past decades
employed different
strategies of antioxidants supplementation, the results were generally
negative in the setting of chronic preventative therapy. Less attention
has
been paid to the modulation of ROS production, despite the fact that
prevention, rather than cure, would appear to be the logic approach to
attenuate
the oxidative damage. There is increasing evidence that endogenous
myocardial uncoupling proteins (UCPs) can play a vital role in
regulating ROS
generation to protect against various pathogenic stresses. Their
expression, which can be induced, may well be a potential therapeutic
target for
various drugs to alleviate the harmful effects of pathogenic processes
and hence modify the progression of cardiovascular diseases (CVDs).
fuel excitation-contraction coupling. More than 90% of cardiac cells
energy is produced in the mitochondria from oxidative phosphorylation
activity
[1]. Oxidative phosphorylation is the process by which energy from fuel
oxidation is converted to the high-energy phosphate bonds of adenosine
triphosphate (ATP). The chemiosmotic hypothesis suggests that the ATP
synthesis is provided by the electrochemical gradient across the inner
mitochondrial membrane. This electrochemical gradient is maintained by
constituents of the electron transport chain (ETC), which acts to pump
protons from the mitochondrial matrix to the intermembrane space of the
mitochondria as they accept and donate electrons in a prescribed manner
Figure. This process of electron transport and oxidative metabolism in
cardiac cells are accompanied by the reduction of oxygen to superoxide
and
other ROS which considered as a by-product of mitochondrial respiration.
An appreciation of the ETC and its role in oxidative
phosphorylation is essential in the understanding of the clinical
significance of UCPs. In the uncoupling process, as the name
suggests, the electrochemical gradient is restored independently
of the activity of ATP synthase [2]. A considerable level of basal
proton leak, also known as global proton leak, occurs across the
inner mitochondrial membrane all the time [3]. While most of this
leak is attributed to the action of uncoupling proteins Figure, the
permeability of the mitochondrial membrane due to the proteins
embedded in its lipid bilayer also contributes to the membrane’s
leakiness. Approximately 20% of the body’s resting metabolic rate
is used to maintain the electrochemical gradient that is dissipated
by this basal proton leak [4]. This significant mitochondrial
proton leak should serve an important function in view of the high
energetic cost utilized to maintain it.
There is increasing evidences show that UCPs, by mitochondrial
uncoupling, protect the heart by reducing ROS generated by the
mitochondria. As a result, cardiomyocyte could be protected
from stress-induced apoptosis [5]. UCP3, in particular, has been
associated with cellular fatty acid metabolism, with its distribution
being most pronounced in muscles with high-fat oxidative capacity
(such as cardiac cells) [6]. In physiological or pathological conditions
where plasma fatty acid levels increase, UCP3 is upregulated.
On the contrary, a decrease in plasma fatty acid levels causes
downregulation of UCP3. These seem to support the hypothesis that
UCP3 plays an important role in exporting fatty acids that cannot
be oxidized from the mitochondrial matrix, thereby inhibiting the
accumulation of fatty acids inside the matrix. In this way, UCP3
provides protection from lipid-induced mitochondrial damage and
mitochondria-dependent apoptosis [6].
UCP expression is regulated in response to externals stressors
by a host of transcription factors. In particular, peroxisome
proliferator-activated receptor alpha (PPARα) and peroxisome
proliferator-activated receptor gamma coactivator 1 alpha
(PGC1-α). Both transcription factors play an essential role in the
response to external environmental stress, such as fasting and
physical stress. Furthermore, activation and/or expression of
UCPs is also closely monitored by intra and extracellular factors.
Regulation may be achieved by enzymes such as AMP-activated
protein kinase (AMPK), proteins such as sterol-responsive elementbinding
protein (SREBP) or nuclear transcription factors such as
PPAR.
Overexpression of UCPs has a beneficial effect on cardiac
energetics regulation, mitochondrial ROS production, calcium
handling and cardiomyocyte apoptosis [7]. Increased UCP
expression could also protect the endothelial cells from the cytotoxic
effect of lysophosphatidylcholine associated with vascular diseases
[8]. However, it may have opposite effects on other CVDs. The
associated decrease in ATP synthesis with overexpression of UCP
may have deleterious consequences on cardiac function and may
worsen the clinical outcomes. Thus, modulation of oxidative stress
through UCPs regulation in CVD as a therapeutic option should be
considered carefully.
The observed downregulation of UCP in heart failure and
subsequent inability of the cell to combat the oxidative burden
caused by the failing heart has led to a potential therapeutic role
of UCP to compact the pathogenesis of the disease. Pathogenesis
of heart failure has been characterized by an increase in ROS
production and ROS-mediated damage. UCPs are known to prevent
ROS accumulation and hence decrease the oxidative burden by
limiting ROS production. Furthermore, UCPs may be involved in
the detoxification of exogenously-produced ROS. In the setting of
heart failure, there is an increase in the concentration of circulating
free fatty acids. This is positively correlated with an increase in
cardiac mitochondrial UCPs. The metabolic effects of UCPs are
cardioprotective in nature and are in fact an adaptive response to
the rise in lipid concentration in the mitochondria [9]. Therefore,
upregulating UCP expression in heart failure could be of therapeutic
benefit.
One of the key regulators of UCP expression in the heart is
PPAR [10]. Hence, to upregulate UCP expression, agonists of PPAR
could be used. Currently few ongoing studies use PPAR agonists
to test their effects on obesity control, diabetes treatment as well
as CVDs. AMPK has been implicated to have a protective role
(anti-apoptotic) as it enhances the survival of cardiomyocytes
in response to ischemia and reperfusion. Loss of AMPK activity
results in an inability to increase glucose uptake and glycolysis by
the cardiomyocytes [11]. Taken together, as a result of AMPK role in
mediating the survival of cardiomyocytes during ischemia, is it also
a potential target for augmenting the expression of UCP in heart
failure.
Another translational approach would be the development
of drugs that would induce UCP expression and hence slow the
progression of atherosclerosis and endothelial dysfunction. The
effects of sitagliptin, a fibrate vegetable extracts, have been shown
to increase the expression of UCP2 with an associated improvement
in mitochondrial biogenesis and function [12]. As such, the
development of a therapeutic agent that modulates oxidative stress
would be of significant impact on vascular diseases.
In conclusion, despite considerable medical interest, the
molecular mechanisms that regulate ROS formation within the
mitochondrion remain poorly investigated. However, increasing
evidence indicates that myocardial UCPs may well play a crucial
role in cellular survival when they are under stress. Myocardial
UCPs may be a potential therapeutic target for the treatment of
cardiovascular disorders in the near future.
None.
No conflict of interest.
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