Oxidative stress and oxidative eustress in the heart
Nearly all human cardiomyopathies are associated with high levels of
reactive oxygen species (ROS), which can cause redox stress in cardiac
tissues 3, 9 . Elevated levels of ROS in cardiac
tissues are also found in many heart failure models in animals1, 9, 15, 29 . By contrast, low levels of the
stable ROS hydrogen peroxide (H2O2) are
critically involved in many physiological signal transduction cellular
pathways in cardiac myocytes 35 and in other
tissues 12, 13, 21, 33 . Indeed, ROS are the
product of normal cellular metabolism– a state termed oxidative
eustress 32 – and may derive from diverse
sources, including mitochondrial electron transport or as the products
of a broad range of intracellular enzymes. Pathological oxidative stress
can derive from mitochondrial dysfunction, from the disruption of redox
metabolism, and as a consequence of cellular inflammatory responses that
lead to the activation of ROS-generating pathways. In many
cardiovascular disease states, pathological oxidative stress is
associated with disrupted cellular energetics, deleterious protein and
DNA alterations, local inflammatory responses, and organ dysfunction3, 16, 20, 29 .
A central problem in modeling oxidative stress derives from the
eponymous reactivity of reactive oxygen species7, 14, 38 . Opening up a bottle of hydrogen
peroxide and pouring out a measured amount of the stuff over cultured
cells does indeed elicit marked changes in cellular pathways- but does
this experimental approach really recapitulate the complexities of
intracellular oxidative stress? Certainly not! Conversely, adding high
concentrations of “antioxidants” to cells can hardly replicate the
convoluted intracellular enzymatic machinery that modulates redox
metabolism. And even the detection of ROS is fraught: many of the assays
and analytic approaches that are intended to detect ROS are plagued by
lack of sensitivity and/or specificity 14 .
These complex considerations undermine experimental approaches that seek
to modulate and to measure oxidative stress in cells, and hamper efforts
to prove that oxidative stress is actually causal for
cardiovascular pathology, instead of merely being associated with
redox derangements. In recent years, the field of redox biology has been
transformed by the advent of new “chemogenetic” approaches to
specifically generate ROS in cells, coupled with the
development of novel biosensors to detect ROS . New insights into
the roles of intracellular oxidants in cardiac function and dysfunction
have emerged from recent studies that have combined chemogenetic
approaches to generate ROS with the quantitation of ROS using highly
specific biosensors.