A key role for mitochondria in endothelial signaling by plasma cysteine/cystine redox potential.
The redox potential of the plasma cysteine/cystine couple (E(h)CySS) 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(h)CySS 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(h)CySS. 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(h)CySS are due to a mitochondrial signaling pathway that is mediated through redox control of downstream effector proteins.
Go
Young-Mi
YM
Division of Pulmonary Medicine, Emory University, Atlanta, GA 30322, USA. ygo@emory.edu
Park
Heonyong
H
Koval
Michael
M
Orr
Michael
M
Reed
Matthew
M
Liang
Yongliang
Y
Smith
Debra
D
Pohl
Jan
J
Jones
Dean P
DP
D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion / Q000235:genetics; D003545:Cysteine / Q000378:metabolism*; D003553:Cystine / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D003553:Cystine; D013879:Thioredoxins; D003545:Cysteine