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Horstkotte, J.* ; Perisic, T. ; Schneider, M.* ; Lange, P.* ; Schroeder, M.* ; Kiermayer, C. ; Hinkel, R.* ; Ziegler, T.* ; Mandal, P.K. ; David, R.* ; Schulz, S. ; Schmitt, S. ; Widder, J.* ; Sinowatz, F.* ; Becker, B.F.* ; Bauersachs, J.* ; Naebauer, M.* ; Franz, W.M.* ; Jeremias, I. ; Brielmeier, M. ; Zischka, H. ; Conrad, M. ; Kupatt, C.*

Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection.

Circulation 124, 2892-2902 (2011)

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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.

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