Sildenafil is a phosphodiesterase type 5 inhibitor indicated in erectile dysfunction and pulmonary hypertension, which confers cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Thioredoxin-1 (Trx1) is a protein which contains redox-sensitive cysteine residues and acts as an antioxidant in cells. The aim of this
study was to determine if Trx1 system participates in cardioprotection exerted by sildenafil in an acute model of I/R, and to evaluate mitochondrial bioenergetics. Langendorff-perfused hearts from wild type mice (WT) and a dominant negative (DN-Trx1) mutant (C32S/C35S) of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) and subjected to 30 min of ischemia followed by 120 min of reperfusion. WT mice treated with sildenafil showed a significantly smaller (41%) infarct size. This protective effect was not observed when sildenafil treatment was administered to DN-Trx1 mice. After I/R, treatment with sildenafil preserved state 3 oxygen consumption from WT mice (137.9±7.6 vs. 140.9±11.0, P<0.05) but had a milder effect in DN-Trx1 mice only partially protecting state 3 values (113.7±3.0 vs. 135.8±7.2, P<0.05). Treatment of WT mice restored respiratory control (RC) after
I/R, which resulted only 8% lower than in basal conditions. The same treatment in DN-Trx1 mice was not as effective as in WT mice and RC values after I/R was 24% lower than in basal conditions. In conclusion, we show that an acute administration of sildenafil reduces not only infarct size but also mitochondrial dysfunction involved
in I/R injury. Our results show for the first time that an active and functional form of Trx1 is necessary for sildenafil to reduce infarct size. Indeed, this fact has great clinical significance, since it is known that several comorbidities or risk factors for the development of ischemic heart disease, such as age, hypercholesterolemia and diabetes are capable of decreasing the activity of Trx1. Therefore, under these circumstances sildenafil would be unable to act as a cardioprotective agent. Further studies need to be performed to fully unravel the mechanism by which Trx1 mediates sildenafil-induced cardioprotection.