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.