Crosstalk Between Mitochondrial and NADPH Oxidase Derived Reactive Oxygen and Nitrogen Species - Implications for Vascular Function

Abstract

Oxidative stress is a well established hallmark of cardiovascular disease and strong evidence for a causal role of reactive oxygen and nitrogen species (RONS) in these processes is based on improvement of cardiovascular complications by genetic deletion of enzymes involved in the synthesis of these reactive species as well as overexpression of antioxidant enzymes detoxifying these reactive species. Vice versa, overexpression of RONS producing enzymes as well as deletion of antioxidant enzymes results in aggravation of cardiovascular complications. With the present overview we present and discuss different pathways how mitochondrial RONS interact (crosstalk) with other sources of oxidative stress, namely NADPH oxidases, xanthine oxidase and an uncoupled nitric oxide synthase. The potential mechanisms of how this crosstalk proceeds are discussed in detail. Several examples from the literature are summarized (including hypoxia, angiotensin II mediated vascular dysfunction, cellular starvation, nitrate tolerance, aging, hyperglycemia, β-amyloid stress and others) and the underlying mechanisms are put together to a more general concept of redox-based activation of different sources of RONS via enzymespecific “redox switches”. Mitochondria play a key role in this concept providing redox triggers for oxidative damage in the cardiovascular system but also act as amplifiers to increase the burden of oxidative stress. Finally, we discuss the role of mitochondrial RONS formation in cardiac disease as well as inflammatory processes but also the role of mitochondria as potential therapeutical targets in these pathophysiological states. Crosstalk between mitochondrial and NADPH