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(American Journal of Pathology. 2007;170:1108-1120.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060960

Endothelial-Specific Expression of Mitochondrial Thioredoxin Improves Endothelial Cell Function and Reduces Atherosclerotic Lesions

Haifeng Zhang^*, Yan Luo^*, Wei Zhang^*, Yun He^*, Shengchuan Dai^*, Rong Zhang^*, Yan Huang^*, Pascal Bernatchez^*, Frank J. Giordano^*, Gerald Shadel, William C. Sessa^* and Wang Min^*

From the Interdepartmental Program in Vascular Biology and Transplantation,^* Boyer Center for Molecular Medicine, and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China; and the Key Laboratory of Combined Multi-Organ Transplantation of Ministry of Health China, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China

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.

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