THIOREDOXIN-1 IS REQUIRED FOR THE CARDIOPROTECIVE EFFECT OF SILDENAFIL AGAINST ISCHEMIA- REPERFUSION INJURY AND MITOCHONDRIAL DYSFUNCTION IN MICE.

TAMARA ZAOBORNYJ; VIRGINIA PEREZ; TAMARA MAZO; ANABELLA GOMEZ; CICALE ELIANA; VERÓNICA CASANOVA; VERÓNICA DANNUNZIO; RICARDO J GELPI

Mar del Plata

Congreso; Reunion conjunta SAIC SAI SAFIS 2018; 2018

Sociedad Argentina de Investigación Clínica

Sildenafil is a phosphodiesterase type 5 inhibitor indicated in erectiledysfunction and pulmonary hypertension, which confers cardioprotection against myocardial ischemia/reperfusion (I/R) injury. Thioredoxin-1 (Trx1) is a protein which contains redox-sensitive cysteineresidues and acts as an antioxidant in cells. The aim of this studywas to determine if Trx1 system participates in cardioprotection exertedby sildenafil in an acute model of I/R, and to evaluate mitochondrialbioenergetics. Langendorff-perfused hearts from wild typemice (WT) and a dominant negative (DN-Trx1) mutant (C32S/C35S)of Trx1 were assigned to placebo or sildenafil (0.7 mg/kg i.p.) andsubjected 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 sildenafiltreatment was administered to DN-Trx1 mice. After I/R, treatmentwith 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 DNTrx1mice 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 effectiveas in WT mice and RC values after I/R was 24% lower than in basalconditions. We show for first time that active Trx1 is required for theonset of the cardioprotective effects of sildenafil on I/R injury and thepreservation of mitochondrial function.