Preventing apoptosis with thioredoxin: ASK me how.

Reactive oxygen species (ROS) are critical signaling molecules in eukaryotic cells, regulating growth, survival, and death pathways. High concentrations of ROS are cytotoxic, but low concentrations can promote growth and activate critical signal pathways in many cell types.1 In the cardiovascular system, significant amounts of ROS are generated as byproducts of mitochondrial metabolism and may increase to toxic levels in the myocardium during and after periods of reduced blood flow. In addition, a number of extracellular peptide hormones are able to increase the production of ROS through receptor-mediated stimulation of membrane-bound NADPH oxidase.2,3⇓ The hypertrophic effects of angiotensin II4 and more recently other G protein–coupled receptor (GPCR) agonists5 have been shown to involve the generation of ROS through this mechanism. In addition, many apoptotic stresses in the cardiac myocyte, including ischemia-reperfusion and high concentrations of NO, signal through ROS. Oxidative stress is a central component of the mitochondrial permeability transition in cardiac myocytes, and the latter seems to underlie most pathologically relevant examples of cardiac myocyte apoptosis in vivo.6 Consequently, a clear understanding of the relationship between myocardial growth and apoptosis signaling will require a better understanding of the intracellular signals that respond to ROS. In this issue of Circulation Research , Liu and Min7 shed light on a fascinating redox-sensitive mechanism that can generate both apoptotic and hypertrophic signals in the cardiovascular system. Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is an upstream activator of p38 MAP kinases and c-Jun N-terminal kinases (JNKs) through MKK3/6 and MKK7, respectively.8 ASK1 itself is activated in cells undergoing various types of stress, including oxidant and cytokine exposure. ASK1 associates with TRAF2 during tumor necrosis factor-α (TNF-α) signaling and is required both for TNF-α–induced apoptosis and …

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