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

Abstract

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.

mt-Nd2 Suppresses Reactive Oxygen Species Production by Mitochondrial Complexes I and III

“…In the presence of mt-Nd2 a , neither complex I nor complex III ROS production was elevated in the context of either ALR or NOD nuclear DNA. We hypothesize that this lowered ROS production is a key mechanistic effect provided by mt-Nd2 a in resistance to various pathological conditions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)18). This hypothesis is supported by the finding that mice encoding mt-Nd2 c exhibit heightened susceptibility to alloxan-induced diabetes (39).…”

“…Reactive oxygen species (ROS) 2 play an important role in the pathologies of many diseases such as atherosclerosis (1)(2)(3)(4)(5), myocardial infarction (6,7), and hypertension (8,9) due to the ability of ROS to damage lipids, protein, and DNA. ROS production has also been associated with the process of aging (10 -12).…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…54 Impaired activity and/or decreased expression of mitochondrial electron transport chain complexes I, III and IV have been implicated in vascular aging and cardiovascular disease, 55 and an association between mitochondrial dysfunction and blood pressure has been reported in human and experimental hypertension. [56][57][58] Ang II-sensitive hypertension is also linked to mitochondrial-derived oxidative stress, as AT 1 receptor blockade attenuates H 2 O 2 production 59 and mitochondrial dysfunction in SHR, and in mice, Ang II infusion is associated with decreased expression of cardiac mitochondrial electron transport genes. 60 In deoxycorticosterone acetate-salt hypertension, mitochondrial-derived ROS, via endothelin-1/endothelin A receptors, has an important role in oxidative vascular damage.…”

Thioredoxins, Mitochondria, and Hypertension

“…However, a recent in vitro study by Liang and Pietrusz 16 provides further support for the hypothesis of Zhang et al 1 They performed a complementary set of experiments using siRNA-mediated Trx2 knockdown in human umbilical vein endothelial cells and found decreased eNOS expression and decreased nitrite/nitrate accumulation associated with increased ROS. 16 Because Trx2 ϩ/Ϫ mice are viable, 13 investigation of these mice is also likely to be important for understanding the physiological importance of Trx2 in vessel reactivity.…”

“…1 Intriguingly, the authors noticed that the mice had higher NO levels and lower resting blood pressure. To investigate whether this association was causal, they performed aortic ring experiments demonstrating that the aortas of the transgenic mice have more dilation because of increased NO levels.…”