Metabolic control and oxidative stress in pathological cardiac remodelling

This editorial refers to ‘Sirtuin 4 accelerates angiotensin II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity’, by Y. Luo et al ., on page doi:10.1093/eurheartj/ehw138. A great deal of scientific evidence points to diverse roles of reactive oxygen species (ROS) in cardiac physiology and pathology.1 These highly reactive, short-lived molecules (superoxide, hydroxyl radical, and hydrogen peroxide) emerge within the cell as natural by-products of the metabolism of oxygen; they derive largely from oxidative phosphorylation in mitochondria, enzymatic reactions, the unfolded protein response, and peroxisomes. Like many things in biology, ROS accomplish critical functions in physiology, including signalling and stress responsiveness, when their abundance is tightly regulated. However, when ROS accumulate, owing either to overproduction or to diminished degradation, they wreak considerable havoc around the cell. A large literature base points to the role of oxidative stress in the pathophysiology of cardiac hypertrophy and, in fact, virtually all forms of cardiovascular disease. Importantly, much of this evidence derives from pre-clinical models. Sadly, when these basic observations have been translated into the human context as antioxidant clinical trials, uniform failure has been observed.2 Whereas an explanation for this consistent failure is obscure, blanket suppression of ROS across the entire cell does not take into consideration the fact that intracellular redox homeostasis is highly compartmentalized; targeting ROS across the cytoplasm and in all tissues may not be …