A key role for mitochondria in endothelial signaling by plasma cysteine/cystine redox potential

• Type of Material: Article
• Authors: Young-Mi Kanggo, Emory University; Heonyong Park, Emory University; Michael H Koval, Emory University; Michael Orr, Emory University; Matthew Reed, Emory University; Yongliang Liang, Emory University; Debra Smith, Emory University; Jan Pohl, Emory University; Dean P Jones, Emory University
• Language: English
• Date: 2010-01-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.freeradbiomed.2009.10.050
• Title of Journal or Parent Work: Free Radical Biology and Medicine
• ISSN: 0891-5849
• Volume: 48
• Issue: 2
• Start Page: 275
• End Page: 283
• Grant/Funding Information: This work was supported by NIH Grants ES011195, ES009047, and HL083120.
• Keywords: Redox ICAT; Mitochondrial thioredoxin 2; Actin; Cytoskeleton; Proinflammatory signaling; Free radicals; Extracellular redox state; Redox proteomics; Endothelial cells
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

The redox potential of the plasma cysteine/cystine couple (EhCySS) is oxidized in association with risk factors for cardiovascular disease (CVD), including age, smoking, type 2 diabetes, obesity, and alcohol abuse. Previous in vitro findings support a cause–effect relationship for extracellular EhCySS in cell signaling pathways associated with CVD, including those controlling monocyte adhesion to endothelial cells. In this study, we provide evidence that mitochondria are a major source of reactive oxygen species (ROS) in the signaling response to a more oxidized extracellular EhCySS. This increase in ROS was blocked by overexpression of mitochondrial thioredoxin-2 (Trx2) in endothelial cells from Trx2-transgenic mice, suggesting that mitochondrial thiol antioxidant status plays a key role in this redox signaling mechanism. Mass spectrometry-based redox proteomics showed that several classes of plasma membrane and cytoskeletal proteins involved in inflammation responded to this redox switch, including vascular cell adhesion molecule, integrins, actin, and several Ras family GTPases. Together, the data show that the proinflammatory effects of oxidized plasma EhCySS are due to a mitochondrial signaling pathway that is mediated through redox control of downstream effector proteins.