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

• Published in: Free radical biology & medicine Vol. 48; no. 2; pp. 275 - 283
• Main Authors: Go, Young-Mi, Park, Heonyong, Koval, Michael, Orr, Michael, Reed, Matthew, Liang, Yongliang, Smith, Debra, Pohl, Jan, Jones, Dean P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.01.2010
• Subjects: Actin; Animals; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Cardiovascular Diseases - physiopathology; Cell Adhesion - genetics; Cysteine - metabolism; Cystine - metabolism; Cytoskeletal Proteins - metabolism; Cytoskeleton; Endothelial cells; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Extracellular redox state; Free radicals; Humans; Mass Spectrometry; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial thioredoxin 2; NIH 3T3 Cells; Oxidation-Reduction; Oxidative Stress; Proinflammatory signaling; Proteomics; Reactive Oxygen Species - metabolism; Redox ICAT; Redox proteomics; Signal Transduction - genetics; Thioredoxins - genetics; Thioredoxins - metabolism; E hCySS; GSSG; Free radicals; DTT; DCF; AMS; Proinflammatory signaling; Redox ICAT; Endothelial cells; ICAT; CVD; MAEC; Redox proteomics; Tg; NLS; Extracellular redox state; Actin; CySS; ROS; Cytoskeleton; Mitochondrial thioredoxin 2; Trx; GSH; WT
• DOI: 10.1016/j.freeradbiomed.2009.10.050
• ISSN: 0891-5849

The redox potential of the plasma cysteine/cystine couple ( E hCySS) 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 E hCySS 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 E hCySS. 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 E hCySS are due to a mitochondrial signaling pathway that is mediated through redox control of downstream effector proteins.