Transmitting biological information using oxygen: Reactive oxygen species as signalling molecules in cardiovascular pathophysiology

The involvement of reactive oxygen species (ROS) in deleterious processes such as DNA damage and reperfusion injury has long been recognized. More recently, however, it has been appreciated that ROS can specifically modulate diverse intracellular signalling pathways through covalent modifications of target molecules (“redox signalling”), thereby inducing distinct changes in cell phenotype that are important in many physiological and pathophysiological processes [1]. Indeed, some ROS such as H2O2 may be ideally suited to serve as signalling molecules in that they are small, highly diffusible, and rapidly generated and degraded. Despite an exponentially growing amount of information on the sources and mechanisms of ROS generation as well as their degradation by the antioxidant defence system, we are just starting to learn how ROS signalling may function within cells and in a coordinated way within tissues and organs. The numerous sources of ROS generation, which include the mitochondrial respiratory chain and enzymes such as the NADPH oxidases (Noxs), xanthine oxidase, uncoupled nitric oxide (NO) synthases, 5-lipooxygenase, and cyclooxygenases, are counterbalanced by a large number of endogenous antioxidants and antioxidant enzymes. This raises the question of how individual ROS could specifically govern diverse signalling events and thereby regulate, in the cardiovascular system, physiological processes such as endothelial migration, vascular smooth muscle proliferation, and angiogenesis, as well as initiate pathophysiological modifications of tissue and organs, resulting in atherosclerosis, hypertension, cardiac hypertrophy, and cardiac and vascular remodelling. One possible answer could be the cell type-specific and subcellular localization of ROS sources and sinks which may allow spatial targeting of ROS to protein adaptor molecules which, after redox modification and subsequent structural change, could then further transmit the redox signal downstream. Indeed, distinct subcellular localization of Nox isoforms has recently been suggested to occur in vascular smooth muscle cells with differential compartmentalization in specific signalling domains in the membrane and focal adhesions [2]. Another view could be that concentration gradients of antioxidant molecules exist in cells and tissues that regulate a distinct flow of ROS by forming spatially distinct “broad highways” and “narrow alleys” of ROS fluxes towards specific targets of high versus low redox sensitivity. Gradients in intracellular pH and oxygen concentration might also be transduced into site-specific ROS generation; e.g., ROS generation beneath plasma membranes could be facilitated by low, submembranous pH levels [3] or – rather paradoxically – gradients of hypoxia could be transformed at sites of pronounced ROS generation [4–6].