Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection

Abstract

Background— Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury. Methods and Results— In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen ( Txnrd2-/-ic ), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours). Txnrd2-/-ic was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered. Conclusions— We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

“…TXN2 regulates cellular redox state and survival by suppressing mitochondrial ROS generation and by inhibiting apoptosis stress kinase-1-dependent apoptotic signaling (16). TXRD2 was shown to play a crucial role during postischemic reperfusion via thiol regeneration (15). Txn1 and its reductase mRNA levels did not change in any of the hypoxic regimens used in this study.…”

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

“…An additional group of C57BL/6 mice received 1 × 10 12 virus particles in the tail vein for cardiomyocyte-specific transduction (Supplemental Figure 3, D-G, and Supplemental Methods). Echocardiographic imaging was repeated at 18 and 24 weeks followed by a LV catheterization using a Millar-Tip catheter (SPR-671, Millar Instruments) to determine the LV developed pressure and LV end-diastolic pressure (40). For evaluation of pressure-volume relationships, an impedance-micromanometer catheter (Millar Instruments) was placed the same way, and pressure-volume loops were recorded (41).…”

Endothelial Dysfunction, and A Prothrombotic, Proinflammatory Phenotype Is Caused by Loss of Mitochondrial Thioredoxin Reductase in Endothelium

“…21 Thus, 2 mutations in the flavinadenine dinucleotide-binding domain of human TXNRD2 have been observed in some patients with dilated cardiomyopathy, 22 and we and associated laboratories have confirmed this enzyme's importance in the heart in a cardiomyocytespecific knockout mouse. 21,23,24 Having successfully generated a Tamoxifen-inducible, EC-specific Txnrd2 knockout mouse (Txnrd2 iECKO ), we hypothesized that elevated ROS originating from the mitochondria of ECs will affect general vascular function and impair vascular remodeling processes in a model of femoral artery ligation. Mice with an EC-specific deletion of Txnrd2 have delayed perfusion recovery after ligation of the femoral artery because of defects in both arteriogenesis in the adductor muscle and angiogenesis in the calf muscle.…”