Endothelial-specific expression of mitochondrial thioredoxin improves endothelial cell function and reduces atherosclerotic lesions.
The function of the mitochondrial antioxidant system thioredoxin (Trx2) in vasculature is not understood. By using endothelial cell (EC)-specific transgenesis of the mitochondrial form of the thioredoxin gene in mice (Trx2 TG), we show the critical roles of Trx2 in regulating endothelium functions. Trx2 TG mice have increased total antioxidants, reduced oxidative stress, and increased nitric oxide (NO) levels in serum compared with their control littermates. Consistently, aortas from Trx2 TG mice show reduced vasoconstriction and enhanced vasodilation. By using ECs isolated from Trx2 TG mice, we further show that Trx2 increases the capacities of ECs in scavenging reactive oxygen species generated from mitochondria, resulting in increases in NO bioavailability in ECs. More importantly, Trx2 improves EC function and reduces atherosclerotic lesions in the apolipoprotein E-deficient mouse model. Our data provide the first evidence that Trx2 plays a critical role in preserving vascular EC function and prevention of atherosclerosis development, in part by reducing oxidative stress and increasing NO bioavailability.
Zhang
Haifeng
H
Interdepartmental Program in Vascular Biology and Transplantation, Department of Pathology, Yale University School of Medicine, BCMM 454, 295 Congress Ave., New Haven, CT 06510, USA.
Luo
Yan
Y
Zhang
Wei
W
He
Yun
Y
Dai
Shengchuan
S
Zhang
Rong
R
Huang
Yan
Y
Bernatchez
Pascal
P
Giordano
Frank J
FJ
Shadel
Gerald
G
Sessa
William C
WC
Min
Wang
W
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation
D001057:Apolipoproteins E; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D013879:Thioredoxins