Exogenous thioredoxin reduces inflammation in autoimmune myocarditis.

Abstract

Levels of reactive oxygen species (ROS) are tightly regulated in mammalian cells. A variety of enzymes produce ROS, including NAD(P)H oxidase, xanthine oxidase, glucose oxidase, myeloperoxidase, the family of nitric oxide synthases, and mitochondrial enzymes.1–4 Low levels of ROS such as superoxide or hydrogen peroxide regulate highly specific targets.5,6 In the cardiovascular system, for example, ROS serve as signaling molecules, mediating vascular endothelial growth factor signal transduction, activating matrix metalloproteinases, and regulating cell cycle phosphatases. Host defenses that protect against oxidative stress include small antioxidant molecules such as ascorbate, α-tocopherol, glutathione, and thioredoxin (Trx), as well as antioxidant enzymes such as superoxide dismutase, catalase, paraoxonase, glutathione reductase, glutathione peroxidase, and Trx reductase. See p 1276 However, excessive oxidative stress—caused by either increased ROS production or inadequate antioxidant defenses—can lead to cardiovascular diseases. For example, genetic deficiency of glutathione peroxidase-1 is associated with increased levels of vascular hydrogen peroxide and arterial thrombosis.7,8 Another example of an imbalance in oxidant stress occurs when elevated levels of angiotensin II trigger excess ROS production by the vascular NAD(P)H oxidase Mox1, contributing to decreased nitric oxide bioavailability, endothelial dysfunction, and atherogenesis.9,10 Additionally, increased levels of ROS generated by xanthine oxidase in the heart impair cardiac energetics, playing a role in the development of cardiomyopathy.11,12 Finally, ROS may play …