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Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection.
Circulation ; 124(25): 2892-902, 2011 Dec 20.
Article en En | MEDLINE | ID: mdl-22144571
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Asunto principal: Compuestos de Sulfhidrilo / Daño por Reperfusión Miocárdica / Estrés Oxidativo / Tiorredoxina Reductasa 2 / Mitocondrias Límite: Animals Idioma: En Revista: Circulation Año: 2011 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Colección: 01-internacional Asunto principal: Compuestos de Sulfhidrilo / Daño por Reperfusión Miocárdica / Estrés Oxidativo / Tiorredoxina Reductasa 2 / Mitocondrias Límite: Animals Idioma: En Revista: Circulation Año: 2011 Tipo del documento: Article País de afiliación: Alemania