Identifying Single S-Nitrosothiol Sites With Cardioprotection

Abstract

Ischemia/reperfusion injury contributes to heart damage in coronary artery disease through the production by mitochondria of deleterious reactive oxygen species. Nitric oxide bioactivity ameliorates ischemia/reperfusion injury by suppressing reactive oxygen species production. A study recently published in Nature Medicine reports that administration of a mitochondrially targeted S-nitrosothiol, MitoSNO, results in the S-nitrosylation of a critical Cys residue within ND3 of mitochondrial complex I , thereby inhibiting reactive oxygen species production and diminishing ischemia/reperfusion injury. Coronary artery disease, the leading cause of mortality in the United States,1 is caused by the blockage of blood vessels in the heart. The resultant ischemia underlies morbidity ranging from angina to myocardial infarction. However, restoration of blood flow (eg, by angioplasty) can lead to the injurious generation of reactive oxygen species (ROS) in cardiac muscle, which results from uncoupling of electron transport in mitochondria.2 The resultant pathology, known as ischemia/reperfusion (I/R) injury, has been characterized in numerous other organs and tissues as well, including brain, liver, kidney, and endothelium.3,4 Nitric oxide (NO), generated by cardiac-resident NO synthases, is considered to play an important role in amelioration of I/R injury.5 In particular, it has been reported that NO bioactivity mediates the protective effects of myocardial ischemic preconditioning (IPC),6 which refers to the ability of short periods of ischemia followed by reperfusion to confer protection against subsequent I/R injury.7 IPC operates, at least in part, by inhibiting electron transport and thereby suppressing ROS generation on reperfusion, and a well-studied effect of NO in mitochondria is the inhibition of complex I (the first stage in the electron transport chain).8 Complex I is responsible for oxidation of matrix NADH by membrane-bound ubiquinone and is the major entry point for electrons to the respiratory chain and, thus, when active, is a …